cord-000008-3dgjv0x1	2008	In response to stimulation with HIV peptide pool, untreated co-infected individuals showed significantly higher frequencies of intra-hepatic CD4 + T-cells producing IFN-c, compared to HCV mono-infected [0.1660.05% vs 0.0260.01%, p,0.05], and HAART-treated co-infected individuals [0.1660.05% vs 0.0360.05%, p,0.05] (Figure 2a ). Therapy naïve co-infected subjects had greater IFN-c producing CD8 + T-cells in response to HIV peptides compared to HCV mono-infected individuals [1.3960.37% vs 0.0260.0%, p,0.05], and HAART was associated with a significant reduction in the frequencies of these cells [1.3960.37% vs 0.3060.26%, p,0.05] (figure 2b). The tetramer cytokine response pattern was shown to be different in the liver compared to blood of the same individual, with diminished intra-hepatic tetramer-specific IFN-c responses and an increase in both CD107a and TNF-a responses, with the majority of SL9 tetramer positive cells expressing these two markers. Therapy naïve co-infected individuals demonstrated a higher frequency of intra-hepatic CD8 + T-cells that produce TNF-a in response to both HCV and HIV antigen stimulation compared to HCV mono-infected individuals.
cord-000083-3p81yr4n	2009	R. China Background: The objective of this study was to evaluate the early virologic response for prediction of achievement of HBeAg seroconversion and hepatitis B virus (HBV) DNA negativity after two years of lamivudine treatment in chronic hepatitis B (CHB) patients. Methods: A total of 620 patients who tested positive for hepatitis B surface antigen and were referred to Chiba University Hospital between February 1985 and March 2008 were included in the study, and their following characteristics were analyzed: age, gender, the status of HBeAg, ALT, HBV-DNA level, and PLT. Methods: A total of 60 patients with chronic hepatitis B, 32 (53.3%) were HBeAg positive (group A) while 28(46.7%) were HBeAg negative (group B) were included in this study after meeting the following criteria: age 18 to 60 years, HBsAg positive for more than 6 months, serum HBV-DNA was >5 log(10) copies/mL and ALT more than two times the upper normal limit.
cord-000174-mgj9zfft	2009	Pulmonary toxicity in patients undergoing HCV combination treatment is rare, and may include interstitial pneumonitis, sarcoidosis, pleuritis, bronchiolitis obliterans organizing pneumonia (BOOP), and exacerbation of asthma [6, 7] . Interstitial pneumonitis occurs only rarely as a side-effect of HCV combination treatment and often leads to discontinuation of therapy, which has great implications for patients. In this article we presented our case of pneumonitis during combination therapy and performed a review in order to generate guidelines to manage symptoms and treatment. In most cases, symptoms of pneumonitis are reversible after cessation of treatment with (peg)interferon and ribavirin, again in support of drug-induced interstitial pneumonitis. Severe interstitial pneumonitis secondary to pegylated interferon alpha-2b and ribavirin treatment of hepatitis C infection Interstitial pneumonitis associated with pegylated interferon alpha-2b therapy for chronic hepatitis C. Interstitial pneumonitis during combination therapy with interferon-a and ribavirin in a patient with chronic hepatitis C Interstitial pneumonitis after combination therapy with pegylated interferon alpha-2b and ribavirin for chronic hepatitis C
cord-000473-jpow6iw1	2011	High-throughput sequencing is a promising approach to characterizing viral diversity, but unfortunately standard assembly software was originally designed for single genome assembly and cannot be used to simultaneously assemble and estimate the abundance of multiple closely related quasispecies sequences. Results: In this paper, we introduce a new Viral Spectrum Assembler (ViSpA) method for quasispecies spectrum reconstruction and compare it with the state-of-the-art ShoRAH tool on both simulated and real 454 pyrosequencing shotgun reads from HCV and HIV quasispecies. Results: In this paper, we introduce a new Viral Spectrum Assembler (ViSpA) method for quasispecies spectrum reconstruction and compare it with the state-of-the-art ShoRAH tool on both simulated and real 454 pyrosequencing shotgun reads from HCV and HIV quasispecies. Given a collection of 454 pyrosequencing reads generated from a viral sample, reconstruct the quasispecies spectrum, i.e., the set of sequences and the relative frequency of each sequence in the sample population.
cord-000638-ss1435el	2012	The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFNα therapy. In contrast, Arizcorreta and colleagues showed that IFNa and ribavirin therapy induces a substantial reduction of circulating sjTRECs, in HIV/HCV co-infected patients, accompanied by sustained naïve CD4 + T-cell defect, suggesting thymic dysfunction [10] . While the number of RTEs was similar in HCV-infected patients at study entry and healthy individuals ( These data demonstrate that, as early as one month following treatment initiation, IFNa induces stronger alterations of naïve Tcell subsets, and more specifically in the RTE compartment than in any other T-cell subset, suggesting a specific effect on thymopoiesis.
cord-000786-ofpcgxce	2012	Although many studies provide strong evidence supporting the development of HCV virus-like particle (VLP)-based vaccines, the fact that heterologous viral vectors and/or multiple dosing regimes are required to induce protective immunity indicates that it is necessary to improve their immunogenicity. Virus-like particles (VLPs) possess features which make them ideal vehicles for the delivery of viral antigens to the immune system; (i) antibody epitopes are presented in the native conformation for induction of potentially neutralising antibodies (ii) multiple T cell, CD4 + and CD8 + , epitopes are packaged in VLPs (iii) VLPs lack regulatory proteins as well as genetic material that could pose a risk of reversion or mutation (iv) encouraging results have been obtained using insect cell-derived recombinant VLPs expressing HCV antigens which induce virus-specific humoral and cellular responses [16] [17] [18] (v) HCV VLPs appear to possess properties favourable for dendritic cell uptake [19] and (vi) they exhibit superior immunogenicity and antigenicity over recombinant protein and DNA-based vaccine approaches [16, 17] .
cord-000830-jiy4cp4n	2012	The use of amplification techniques such as polymerase chain reaction, real-time polymerase chain reaction or nucleic acid sequence-based amplification for virus detection, genotyping and quantification have some advantages like high sensitivity and reproducibility, as well as a broad dynamic range. The use of amplification techniques such as polymerase chain reaction (PCR), real-time PCR or nucleic acid sequence-based amplification (NASBA) [3] for virus detection, genotyping and quantification have some advantages like high sensitivity and reproducibility, as well as a broad dynamic range [4, 5] . NASBA assays could identify active infection by detecting viral messenger RNA (mRNA) but the most widely used tests in clinical virus diagnosis are quantitative real-time PCR techniques [8] . Some real-time PCR assays such as LightCycler parvovirus B19 quantitative assay (Roche Diagnostics, Indianapolis, IN) and ABI TaqMan (Applied Biosystems) have been developed for detecting B19 nucleic acids in association with infection during pregnancy or assessing the prevalence of the virus DNA in blood products [62, 63] .
cord-000833-m6abyuvx	2012	The HCV core protein was expressed consistently in the liver after polyinosinic acid–polycytidylic acid injection, and these mice showed chronic hepatitis C-related pathological findings (hepatocyte abnormalities, accumulation of glycogen, steatosis), liver fibrosis, and hepatocellular carcinoma. These observations, in addition to the modified histology activity index (HAI) scores, indicated that expression of HCV proteins caused chronic hepatitis in the CN2-29 (+/2) /MxCre (+/2) mice because a weak, though persistent, immune response followed an initial bout of acute hepatitis ( Figure S1 ). To determine whether activation of the host immune response caused the reduction with HCV protein levels in the livers of CN2-29 (+/2) /MxCre (+/2) mice, we used a highly attenuated VV strain, LC16m8, to generate three rVVs [12] . To determine whether rVV-N25 treatment induced the same effect in other strains of HCV transgenic mice, we analyzed RzCN5-15 (+/2) /MxCre (+/2) mice, which express all HCV proteins; in these mice, chronic hepatitis was resolved within 28 days of immunization with rVV-N25.
cord-001421-6t5puo6p	2014	The serum proteomic profile and routine liver and renal function tests were initially analyzed in a training set of 10 HCV-RNA recurrent LT patients 6 months post LT that showed a fibrosis stage F$1 at 1 year after LT. HVPG was assessed in 53 of these patients and the average value was of 5.560.8 mm Hg. All the serum samples showed a quite similar expression pattern and coincidences included both the different peptide fragments detected and the signal intensity of these fragments (Data S4). All serum samples included in the test set showed an intensity m/z 5905 peak well below the values found in both healthy subjects and non recurrent HCV patients. In conclusion, we identified a 5.9 kDa C-terminal fragment of the fibrinogen a chain as a serum biomarker of early fibrogenic processes in patients with liver disease. In conclusion, we identified a 5.9 kDa C-terminal fragment of the fibrinogen a chain as a serum biomarker of early fibrogenic processes in patients with liver disease.
cord-001834-6xf4o3oy	2015	In HCV-infected cells, viral RNA is sensed by retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5) in the cytoplasm and Toll-like receptor 3 (TLR3) in the endosome, which leads to downstream signaling that results in the induction of type III and I IFNs and other inflammatory cytokines [28, [36] [37] [38] [39] . Intracellular signals from RIG-I, MDA-5, and TLR3 are transmitted via mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1 receptor domain-containing adaptor inducing IFN- (TRIF), respectively, which leads to the interferon regulatory factor-3 (IRF-3)-dependent induction of IFNs and NF-κB activation in HCV-infected cells [38, 39] . IFN-s activate the same JAK-STAT pathway as type I IFNs [48] [49] [50] , thereby inducing a similar set of ISGs. Although the exact source of IFN-s in HCV-infected liver remains to be clarified, it seems that the production of IFN-s by HCV-infected hepatocytes results in the expression of ISGs, presumably through autocrine and/or paracrine signaling via the IFN-λ receptor [28, [44] [45] [46] . HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons
cord-001848-idmj2d7p	2015	We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Previously, we showed that transient transfection of an expression construct that generates IFN-l4 protein induced interferon signaling, with activation of interferon-stimulated genes (ISGs) and generation of antiviral response in HepG2, a human hepatoma cell line (Prokunina-Olsson and others 2013). The stable HepG2-ISRE-Luc cells were transfected with corresponding constructs in 96-well plates; untransfected cells were treated with human recombinant interferons-IFNa (2 ng/mL; PBL Assay Science) or custom IFN-l3 (10 ng/ mL). Previously, by performing Western blot analysis, we were unable to detect IFN-l4 in culture media of HepG2 cells transiently transfected with an IFN-l4-producing construct, even though this transfection resulted in strong activation of interferon signaling (Prokunina-Olsson and others 2013). IFN-l4 was detectable in culture media of IFNL4-transfected PHHs and HepG2 cells, but not in corresponding Halo-transfected cells (Fig. 2B) .
cord-002369-shk4n8f6	2017	The expression of HCV proteins results in the induction of a major rearrangement of host cell membranes, thus leading to the formation of a complex membranous compartment termed the membranous web (MW), which favors viral RNA replication and assembly 3, 4 . To determine whether LC3 or the ATG5-12 conjugate modulates HCV RNA replication, we analyzed the effects of silencing these autophagy genes on viral RNA replication in Huh7 cells stably expressing the JFH1 subgenomic replicon (SGR). Because silencing of LC3 expression led to a clear inhibition of HCV RNA translation after electroporation of the viral RNA but did not significantly affect replication in JFH1-SGR cells, we sought to compare the effect of siRNA treatment before and after infection with HCVcc JFH1 (Fig. 3C) . The autophagy elongation complex proteins (ATG5-12 and ATG16L1) were also detected in the purified MW from NS4B HA replicon cells, but not in the control extract, thus indicating that the elongation complex is indeed present at the HCV replication site.
cord-002410-2zi5iv2t	2017	Among the three classes of IFNs, type III IFNs, also called IFN lambdas (IFNLs), are an essential component of the innate immune response to hepatitis C virus (HCV). Here, we will review our current knowledge on IFNL gene expression, protein properties, signaling, ISG induction, and its implications on HCV infection and treatment. Type III IFNs and ISGs are similarly inducted upon HCV infection of primary human fetal liver cells [98, 99] . In summary, expression of specific IFNL subtypes is induced in PHH and some hepatoma cell lines upon infection with HCV, resulting in limiting virus production. Viral infection and toll-like receptor agonists induce a differential expression of type I and interferons in humans plasmacytoid and monocyte-derived dendritic cells HepG2 cells mount an effective antiviral interferon-lambda based innate immune response to hepatitis C virus infection HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons
cord-002774-tpqsjjet	2017	Results: The CHIP Framework The CHIP framework aims to improve the health and wellness of the urban communities served by St. Josephs Health Centre through four intersecting pillars: • Raising Community Voices provides an infrastructure and process that supports community stakeholder input into health care service planning, decision-making, and delivery by the hospital and across the continuum of care; • Sharing Reciprocal Capacity promotes healthy communities through the sharing of our intellectual and physical capacity with our community partners; • Cultivating Integration Initiatives facilitates vertical, horizontal, and intersectoral integration initiatives in support of community-identified needs and gaps; and • Facilitating Healthy Exchange develops best practices in community integration through community-based research, and facilitates community voice in informing public policy.
cord-003158-mhlqnj52	2018	Previous studies have demonstrated that the HCV JFH1 NS5A C-terminal is a flexible region which is capable of accommodating foreign gene inserts (such as EGFP, 720bp and Rennilla luciferase [Rluc] , 930bp) and still permit HCV replication and viral production (18, 19, (24) (25) (26) (27) (28) (29) . In this study, we used the JFH1-AM120 as a vector to explore if infectious reporter virus would be produced following insertion of LacZ gene that was three time larger than Rluc, into the NS5A C-terminus. This result provided evidence that fusion protein of NS5A and β-galactosidase can be co-expressed in Huh7.5 cells after transfection of JFH1-AM120-LacZ RNA. Our results demonstrate that the LacZ reporter gene can be inserted into the NS5A C-terminus of HCV JFH1-AM120 and will express the predicted NS5A-LacZ fusion protein, which can be detected by western blotting three days after RNA transfection of cells.
cord-003407-f5v3hhr8	2018	Thus, RC''s anti-HCV activity appeared strongest when concurrently present on the host cell with the viral particles, suggesting that its inhibitory effect mainly targeted the early phase of the HCV infection, including viral entry. Viruses 2018, 10, x FOR PEER REVIEW 6 of 12 strongest when concurrently present on the host cell with the viral particles, suggesting that its inhibitory effect mainly targeted the early phase of the HCV infection, including viral entry. To further characterize the mechanism(s) underlying RC''s anti-HCV effect, which was strongest when RC was simultaneously present with the virus on the host cell surface, we performed a synchronized infection assay on early viral entry. To further characterize the mechanism(s) underlying RC''s anti-HCV effect, which was strongest when RC was simultaneously present with the virus on the host cell surface, we performed a synchronized infection assay on early viral entry.
cord-003993-3bozjfv7	2019	Technological advances that allow throughput sequencing of viral genomes, as well as the development of computational tools to analyze such genome data, have largely expanded our knowledge on the host range and evolutionary history of human hepatitis viruses. This finding, as well as the increasing availability of the genome sequences of human-infecting viruses sampled across different geographic areas, has largely expanded our knowledge about the genetic diversity and evolutionary origin of these human pathogens. Studies that did not account for the TDRP provided estimates of the time to the most recent common ancestor (TMRCA) of HCV genotypes in a range between $200 and 1000 years ago [63, 64, 76, 87, 88] ; the origin of the horse virus was dated around 1800 CE [85] . Although several human hepatitis E cases have a zoonotic origin and orthohepeviruses A are found in diverse mammals, recent data indicated that one or more reverse zoonoses led to the emergence and radiation of HEV genotypes [121] .
cord-005138-u2lwgyyf	2006	title: Hepatitis C virus NS4A inhibits cap-dependent and the viral IRES-mediated translation through interacting with eukaryotic elongation factor 1A In this study, we have demonstrated that NS4A specifically interacted with eukaryotic elongation factor 1A (eEF1A) and inhibited both cap-and HCV IRES-dependent protein synthesis. To perform translation inhibition assay in culture cells, plasmids encoding V5-tagged HCV nonstructure proteins NS3, NS4A, NS4B, and NS4A mutants were independently cotransfected with the cap-dependent monocistronic luciferase reporter pCMV-Luc or the bicistronic luciferase reporter pJSS12 into Huh7 cells. To perform cap-dependent in-vitro-translation inhibition assay, GST and GST-NS4A fusion proteins that were recovered from the Sepharose 4B beads as described earlier were preincubated with 5 ll of rabbit reticulocyte lysate (RRL, Promega) at 4°C for 1 h. The results demonstrated that both NS4A and NS4B inhibited HCV IRES-mediated translation to levels similar to those of the cap-dependent translation, whereas no effect was detected with the viral NS3 protein (Figure 2d ).
cord-005617-bxbogskm	2019	This study aims to describe the population being screened for anti-HCV antibodies in the COBATEST Network and identify risk factors associated with a reactive HCV screening test result in the period 2014–2018. This study describes HCV screening activity in CBVCT services, describes the populations being screened, describes the proportion of reactive HCV screening tests and identifies risk factors associated with a reactive HCV screening test result in the COBATEST Network in the years 2014-2018. Secondly, the clients screened for HCV and clients with a reactive screening test were described by socio-demographic characteristics (gender [men, women, transgender], age group [16-24, 25-44, 45-64, > 65], migrants [defined as been born in a country different to the country where the CBVCT service is placed], region of origin), key populations (MSM, PWID, SW) and epidemiological variables (HIV status, HCV screening test results and RNA test results).
cord-006061-z9r5htm9	2016	Altogether, we provide a mechanism by which NS4B induces cell transformation through its PBM, which specifically interacts with the PDZ domains of Scribble and targets Scribble for degradation. Our previous work has shown that NS4B expression activates unfolded protein response (UPR), ER overload response, and NF-κB pathway in human hepatic cells, which could contribute to HCV replication and pathogenesis [11] [12] [13] . As shown in Fig. 5a , expression of HCV NS4B led to reduced USP14 protein levels in both 293T cells and HepG2 cells especially at 48-h post-transfection, indicating that HCV NS4B activates the proteasome-ubiquitin pathway. In this study, we provided a plausible mechanism that NS4B induces cell transformation by degrading the tumor-suppressor protein, Scribble, through the interaction between NS4B PBM and Scribble PDZ domains. The NS4B PBM-Scribble PDZ interaction is important for colony formation of transfected cells, indicating that NS4B PBM contributes to HCV pathogenesis and cellular transformation by inducing Scribble degradation.
cord-006129-5rog0s98	2012	[12] Answering back, certain host miRNAs alter the cell gene expression to defend the cells against the viral infection by interfering with viral proteins or other cellular factors as a type of immune response against these particular viruses. [40] These virus-encoded miRNAs play important roles in the establishment of latent infection, as well as the pathogenesis of virally induced diseases. According to the most recent studies, herpesviruses utilize their encoded miRNAs in a wide range of biologic functions, such as inhibition of apoptosis, immune evasion, control of cellular proliferation, and regulation of viral replication. [58] Downregulation of UL114 protein, using miR-UL112-1, results in inhibition of viral DNA replication and subsequently triggers the latent phase of infection, making the virus able to evade the host immune system.
cord-006436-61mgtbj4	1993	A new artificial liver support system (ALSS) consisting of plasma exchange (PE) in combination with hemodiafiltration (HDF) using high-performance membranes of polymethyl metacrylate (PMMA) and cellulose triacetate (CTA) was developed to efficiently remove middle molecules from plasma and treat fulminant hepatic failure (FHF) complicated, by the onset of hepatic coma. It is anticipated that this new ALSS will not only be of value in cases of fulminant hepatic failure but that it may also play a role in sustaining life for those, awaiting liver transplantation. Preliminary use of this new ALSS has shown it to be effective in reversing grade V hepatic coma in a patient with fulminant liver failure (15) . A new ALSS system consisting of PE and HDF using high-performance membranes [polymethyl metacrylate (PMMA) and cellulose triacetate (CTA)] was devised to enhance the removal of the middle-Sized molecules thought to be responsible for hepatic coma.
cord-006856-b1w25ob5	2005	Egr-1 and hypoxia-inducible factor-1 (HIF-1) gene expression was examined in left ventricular biopsies of explanted failing hearts in 28 ICM and 42 DCM patients, as well as in 12 donor grafts before reperfusion (control), at 10, 30, 60 minutes after reperfusion, and at 1, 2, 3, 4, 6, 12 posttransplant weeks, using real-time RT-PCR. The risk of transplant-related mortality (TRM) due to graft-versushost disease (GvHD) is higher in male recipients of female stem cells compared with female patients receiving a graft from a female donor. We therefore analyzed a single-center cohort of 72 high-risk patients transplanted with a related or unrelated stem cell graft after nonmyeloablative conditioning for outcome (acute and chronic GvHD, TRM, relapse, and survival). Four patients between the age of 34 and 44 years underwent allogeneic peripheral blood stem cell (PBSC) transplantation (SCT) from HLA-identical sibling or unrelated donors at our institution.
cord-007236-8hiymqyb	2011	title: Inhibition of hepatitis C virus replication by Monascus pigment derivatives that interfere with viral RNA polymerase activity and the mevalonate biosynthesis pathway We demonstrated that a group of Monascus orange pigment (MOP) derivatives effectively inhibited NS5B RdRp activity and interfered with the mevalonate synthesis pathway, thereby suppressing HCV replication in cells harbouring an HCV genotype 1b subgenomic replicon and in cells infected with genotype 2a HCV. As shown in Figure 2 (a), among the selected group of MOP AADs that inhibited NS5B RdRp activity in vitro, Lys, Phe, Val, Leu and Ile derivatives also inhibited HCV replication in Huh7 cells, which harbour a HCV subgenomic replicon RNA. Together, these results suggest that in addition to a direct inhibition of NS5B RdRp activity, these MOP AAD compounds also inhibit HCV replication by interfering with the cholesterol biosynthetic pathway downstream of the HMG-CoA reductase step.
cord-007305-pkjfnhro	1984	COLLEAGUES -Some areas in the northern part of the Israel desert (Negev) are known to be endemic for Borrelia recurrentis infection [1] (tick-borne relapsing fever). None of them developed overt symptoms and signs of tick-borne relapsing fever as observed in the subjects from groups I and II. Our patients had nail abnormalities typical for leukonychia partialis of the acquired type, since color changes had not been noted before the present illness and were transient. We would welcome correspondence from others who have seen nail color abnormalities in Kawasaki disease. COLLEAGUES -We examined paired sera from 62 infants with acute non bacterial gastroenteritis and from 50 age-matched controls (admitted to the hospital for nondiarrheal diseases) for antibody to human coronavirus (HCV) OC43 and neonatal-calf diarrhea coronavirus (NCDCY). Convalescent-phase sera from all the patients positive for excretion of coronavirus-like particles in stools, and seronegative for previous HCV OC43 infections, reacted by IEM with HECY-24 and HECV-35 and, to a lesser extent, with HCY OC43.
cord-007890-bie1veti	2002	Effects of Interferon alpha plus ribavirine therapy on frequencies of HCV, HIV and CMV specific CD4-T-cell responses in peripheral blood of HIV/HCV coinfected patients after 6 months of treatment SoA9.5 Methods: Two groups of patients with chronic HCV infection were studied: 26 HIV coinfected progressors with antiretroviral therapy and 13 HIV-negative controls. In order to assess the local temporal trend of antibiotic sensitivity of the most common urinary tract bacterial pathogen, all urine-cultured Escherichia coli isolates were reviewed as to susceptibility profile, and specimen source (community-versus hospital-acquired infection). Methods: A total of 87 penicillin resistant clinical strains isolated from patients at Hacettepe Children''s Hospital, Ankara, Turkey between 1999 and 2001 were tested for their in vitro susceptibility to various antibiotics that are commonly used in the treatment of respiratory tract infections.
cord-009263-w8bmmgtj	2020	The initial binding step primarily involving the lipoprotein component of LVPs likely is a rather unspecific event, which results in the concentration of the virus at the basolateral membrane of hepatocytes and exposure of viral envelope glycoprotein domains that enable the virus to specifically interact with SR-BI, CD81, and CLDN1 (post-binding). Initial attachment of LVPs to hepatocyte basolateral membranes likely involves virus-associated lipoprotein components (particularly apoE [9,13,30-35]), and virus envelope glycoproteins, which interact with highly sulfated heparan sulfate proteoglycans (HSPG) [36] [37] [38] (particularly syndecans [39] [40] [41] ), LDL receptor (LDLR) [42] [43] [44] [45] and SR-BI [46] [47] [48] [49] [50] [51] on the cell surface ( Figure 1 ). Initial attachment of LVPs to hepatocyte basolateral membranes likely involves virus-associated lipoprotein components (particularly apoE [9,13,30-35]), and virus envelope glycoproteins, which interact with highly sulfated heparan sulfate proteoglycans (HSPG) [36] [37] [38] (particularly syndecans [39] [40] [41] ), LDL receptor (LDLR) [42] [43] [44] [45] and SR-BI [46] [47] [48] [49] [50] [51] on the cell surface ( Figure 1 ).
cord-009567-osstpum6	2008	Introduction: Previously, it has been demonstrated that FOXP3, a gene required for the development and function of regulatory T cells, was highly expressed in the graft during cardiac rejection, suggesting infiltration of regulatory T cells in the transplanted organ during an allogeneic response. Efficacy and safety parameters assessed at follow-up included: acute rejection; patient and graft survival; renal function, vital signs, basic lab results and immunosuppressive regimen for the patients 10 years after completion of the original study. We analyzed, for the first time, the expression of TLR4 in PBMC from kidney recipients with contrasted situations: operational tolerance and chronic immune-mediated rejection (Banff 2005), compared to patients with normal histology and stable graft function, non transplant patients with renal failure and healthy volunteers.
cord-010088-s9tfvtao	2013	These include ''incorrect blood component transfused'' events, where the blood component was intended for another recipient (frequently due to errors in patient identification at the time of collection of the pre-transfusion sample, or at the time of bedside administration), or did not meet the patient''s special needs (such as a patient with a red cell antibody who did not receive the required antigen-negative unit). Methods: Eligibility criteria for inclusion in the study included the following: transfusion of Rh D positive platelets, no anti D detectable before transfusion, no previous exposure to Rh D positive blood components, and results of follow-up testing of anti-D in patients serum available. In addition, the allelic frequency of Hpdel was calculated to be 0.015 by a genetic study of a limited number of the Japanese individuals, suggesting that Hp deficiency might distribute among the Japanese population as a phenotype of serum Hp. Aims: In this report, we present the results obtained from a hemovigilance survey carried out between 1998 and 2012, in which Hp deficiency was identified among Japanese patients who had experienced nonhemolytic TRs (NHTRs), and those obtained from a screening of Hp-deficient Japanese healthy blood donors.
cord-010092-uftc8inx	2019	Prospective testing of blood donations in endemic areas of the U.S. revealed 0.38% of donors were positive for Babesia DNA or antibodies (Moritz, NEJM, 2016) Aims: -To report results of ongoing Babesia clinical trial -To explain significance of Babesia as a TT infection Methods: In cobas â Babesia for use on the cobas â 6800/8800 Systems, is a qualitative polymerase chain reaction nucleic acid amplification test, developed to detect in whole blood (WB) donor samples the 4 Babesia species that cause human disease: B. In sensitivity analyses, there were two discrepant results for HIV testing, three for HCV, and five for anti-HBc. Summary/Conclusions: Elecsys â infectious disease parameters on the cobas e 801 analyser demonstrate high specificity/sensitivity for screening first-time blood donor samples, with similar clinical performance to other commercially available assays.
cord-010119-t1x9gknd	2017	Conclusion: The wide distribution in the concentration of bioactive lipids among 405 stored RBC units suggests that lipid degradation is highly donor-Background/Case Studies: To ensure availability of biological products to hospitals, blood banks have developed and validated multiple storage conditions for each of their products to maximize shelf life and quality. 1 The Department of Blood Transfusion, The PLA General Hospital, 2 The Department of Blood Transfusion, Air Force General Hospital, PLA Background/Case Studies: Recently, multi researches have reported that longer term-stored red blood cells(RBCs) units were associated with increased risks of clinically adverse events, especially in critically ill patients. Weak D types 1, 2 and 3 express all the major RhD epitopes and these patients can be managed as RhD-positive, which may lead to a reduction in unnecessary Rh immunoglobulin (RhIG) administration and conservation of RhD-negative RBCs. Study Design/Method: RHD genotyping was performed on all patient samples with weaker than expected or discrepant RhD typing results, utilizing a commercially available genotyping kit manufactured by Immucor (RHD BeadChip).
cord-010273-0c56x9f5	2001	1,2 The identification of HCV led to the development of diagnostic assays for infection, based either on detection of antibody to recombinant polypeptides expressed from cloned HCV sequences or direct detection of virus ribonucleic acid (RNA) sequences by polymerase chain reaction (PCR) using primers complimentary to the HCV genome. 6 ''13 Remarkably, a series of plant viruses that are structurally distinct from each of the mammalian virus groups, and with different genome organizations, have RNA-dependent RNA polymerase amino acid sequences that are perhaps more similar to those of HCV than are the flaviviruses. In contrast to the highly restricted sequence diversity of the 5''NCR and adjacent core region, the two putative envelope genes are highly divergent between different variants of HCV (Table III) 111-114 and show a three-to-four-times higher rate of sequence change with time in persistently infected patients, ll5 Because these proteins are likely to lie on the outside of the virus, they would be the principal targets of the humoral immune response to HCV elicited on infection.
cord-011026-iapgkz0p	2019	title: Smp76, a Scorpine-Like Peptide Isolated from the Venom of the Scorpion Scorpio maurus palmatus, with a Potent Antiviral Activity Against Hepatitis C Virus and Dengue Virus Smp76 antiviral activity was evaluated using a cell culture technique utilizing Huh7it-1, Vero/SLAM, HCV (JFH1, genotype 2a) and DENV (Trinidad 1751, type 2). For dengue virus infectivity, serially diluted venom fractions and Smp76 were mixed with fixed amount of DENV and incubated for 2 h at 37 °C. The above results suggest that the Smp76 directly affects HCV particles and/or host cells in the culture medium to inhibit the viral infection and does not have an antiviral effect in the cells. To determine whether the antiviral activity of Smp76 peptide (previously described) was specific to HCV and DENV, a Schematic of infection assay. The exact mechanism by which Smp76 exerts its antiviral activity against HCV and DENV to inhibit infecting their target cells need further studies.
cord-011182-nbtfb39r	2019	Our research was based on employing several bioinformatics software applications to find important mutations in domain 1 of core protein in Iranian HCV infected samples from 2006 to 2017, and an investigation of general properties, B-cell and T-cell epitopes, modification sites, and structure of domain 1. In this study, we employed several bioinformatics tools to find important mutations in domain 1 of the core protein, general properties of B-cell and T-cell epitopes, modification sites, and structure of domain 1 in Iranian HCV infected samples from 2006 to 2017. (2002 compared sequences of the core protein of Subtype 1b HCV strains obtained from patients with and without HCC and found some amino acid mutation sites (Ogata et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin Amino acid substitutions in hepatitis C virus core region predict hepatocarcinogenesis following eradication of HCV RNA by antiviral therapy
cord-013176-6ckuya1w	2020	Quercetin, extracted from Embelia ribes (Mirsinaceae), exhibited antiviral effects against HCV, exerted through activity inhibition of the viral protease Non-Structural protein 3 (NS3), leading to a decrease in HCV replication [36] . The natural extract of Tetrastigma hemsleyanum (Vitaceae) contains many flavonoids, including vitexin, vitexin-2-O-rhamnoside, isorhamnetin, rutin, kaempferol, astragalin, quercitrin, quercetin and iso-quercetin, which were shown to be able to exert anti-influenza virus activity, with different efficiency, through the reduction of the number of plaques induced by the influenza virus in infected Madin-Darby Canine Kidney (MDCK) cells [21] . In future perspective, this approach could be considered in order to possibly improve the antiviral activity of some flavonoids, like baicalin, that was able, like fludarabine [65] , to act against HIV-1 chronic infection of human monocytes and macrophages, inhibiting the fusion of HIV virus envelope proteins with these cells [73] .
cord-013244-d6saaiu9	2020	However, it is conceivable that in the near future DAA treatment of HCV-infected women during pregnancy becomes available, not only to limit disease progression in the patient, but also to prevent vertical transmission of the virus to the child. A screening model linked to HCV-disease states within a Markov model was used to evaluate the cost-effectiveness (CE) of HCV screening of pregnant women, with initial treatment during pregnancy, compared to current practice (no screening and no intervention) from a health-care payer perspective in the Netherlands. We subsequently determined the cost-effectiveness and budget impact of HCV screening and treatment among the four cohorts of pregnant women following the different scenarios and comparisons. Our present study demonstrates that HCV screening of pregnant women and subsequent immediate treatment of all HCV-positive individuals with DAAs is a cost-effective intervention in the Netherlands.
cord-015372-76xvzvdg	1996	One, two and five-year survival rates were examined; age at diagnosis and lesion type were extremely significant factors in relation to patient outcome. Patients'' age, sex, risk group, CDC stage, CD4 count, indication for therapy, complication rate and response to treatment are described. Fifty-eight patients (34 male, 24 female) ranging in age from 15 to 65 years (Mean + SD = 28.4 + 10.8) were included in the study. Among these 48 patients (mean age 68.0+12.7), after controlling for age and for the duration and continuity of subsequent antipsychotic treatment, increasing duration of initially untreated psychosis was associated with greater severity of negative symptoms (p<0.005) and with lower scores on the MMSE (p<0.05) but not with executive dysfunction on the EXIT (p=0.3). Conclusion Although not a population based study, care of IDDM in Ireland is almost totally hospital clinic based Cigarette smoking is identified as the major problem to be addressed Patients with diabetes meltitus (DM) are at a higher risk of developing vascular complications, including coronary artery disease (CAD).
cord-015941-4fz79wzf	2018	Through the application of molecular biology, biological and biochemical analyses have been revolutionized, and nucleic acid, gene-based techniques have been developed to screen blood and plasma donations for evidence of very recent and earlier viral infections that might otherwise be missed by conventional serologic testing. Because NAT detects a virus''s genetic material instead of waiting for the body''s response, the formation of antibodies, as with many current tests, it offers the opportunity to reduce the window period during which an infecting agent is undetectable by traditional tests [21] , thus further improving blood safety. One reason for this is that currently available blood screening technologies detect core antibodies or surface antigens, which appear up to 8 weeks after infection. The anti-HBc test developed in 1987 detects an antibody to the hepatitis B virus that is produced during and after infection. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-amplification testing
cord-016343-wc3i54fc	2008	RdRp, RNA-dependent RNA polymerase; IRES, internal ribosome entry site; 5BSL3.2, stem loop 3.2 within the coding sequence of NS5B normally result in the production of type I IFNs and the subsequent expression of IFN-induced effector proteins, which in turn would establish an antiviral state in the IFN-producing cell itself and in neighboring cells. Since MxA has the ability to efficiently inhibit a variety of different RNA viruses, MxA was the first IFN-induced effector protein to be analyzed for its antiviral activity in the HCV replicon system (Frese et al., 2001) . Rather indirect evidence that the OAS/RNase L pathway may indeed target HCV replication/translation was recently provided by Taguchi and co-workers, who reported that the N-terminal portion of NS5A (amino acids 1 to 148), which lacks the so-called PKR-binding domain, binds to OAS proteins and there by counteract the antiviral activity of IFN-α (Taguchi et al., 2004) .
cord-017506-t86v3zw3	2012	Cardiovascular disease is likely due to a combination of additional risk factors found in HIV infection [ 26 ] including (1) chronic in fl ammation from HIV viral replication and subsequent immunode fi ciency [ 134 ] , (2) the effect of chronic in fl ammation on serum lipid levels [ 133 ] , (3) the metabolic effects of certain classes of antiretroviral medications [ 131, 133 ] , (4) increased prevalence of insulin resistance [ 135 ] , and (5) increased translocation of bacteria across the small intestine into the bloodstream as a result of immunode fi ciency [ 136 ] . Freiberg et al., studying the VACS Cohort, found that the risk of cardiovascular disease was increased (OR 1.55, 95% CI 1.07-2.23) in HIV-infected men with alcohol abuse or dependence, when controlled for cardiac risk factors, ART use, and CD4 count [ 8 ] .
cord-017764-h1w9gbxk	2018	A groundbreaking clinical trial that combined daclatasvir (1) with the protease inhibitor asunaprevir (52) established that a chronic HCV infection could be cured with small molecule therapy in the absence of immune stimulation, setting the stage for approval of this regimen for the treatment of GT-1b-infected subjects by the Japanese health authorities on July 4, 2014. The discovery of the hepatitis C virus (HCV) nonstructural 5A (NS5A) replication complex inhibitor daclatasvir (1) began with the development of a genotype 1b (GT-1b) replicon that was implemented as a phenotypic screen using a design that conferred a stringent triaging of hit molecules [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] . A screen of compounds selected from the library of HCV NS5A inhibitors assessed in the presence of 1 using the Tyr93Asn GT-1aresistant replicon, followed by SAR optimization, identified Syn-395 (52) as a molecule capable of restoring the sensitivity of resistant virus to the inhibitory effects of 1. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect
cord-017948-fqhl1qb4	2012	Currently, nucleic acid testing techniques have been developed to screen blood and plasma products for evidence of very recent viral infections that could be missed by conventional serologic tests. Through the application of molecular biology, biological and biochemical analyses have been revolutionized, and nucleic acid, gene-based techniques have been developed to screen blood and plasma donations for evidence of very recent and earlier viral infections that might otherwise be missed by conventional serologic testing. Because NAT detects a virus''s genetic material instead of waiting for the body''s response, the formation of antibodies, as with many current tests, it offers the opportunity to reduce the window period during which an infecting agent is undetectable by traditional tests [ 19 ] , thus further improving blood safety. Detection of HIV-1 and HCV infections among antibody-negative blood donors by nucleic acid-ampli fi cation testing
cord-018220-8m11ig06	2009	The recommendations of the Advisory Committee on Immunization Practices (ACIP) 2007 relating to the elderly, include vaccination of all persons ³ 50 years, vaccination of residents of nursing homes and chronic-care facilities, vaccination of healthcare personnel, and vaccination of healthy household contacts (including children) and caregivers of adults ³ 50 years (3) . In a prospective study from Rochester, NY, using a combination of viral culture, RT-PCR and serology for diagnosis, RSV infection was documented in 3-7% of 608 healthy elderly and 4-10% of adults with chronic cardiopulmonary conditions over four winter seasons (16) . In healthy elderly patients and in adults with chronic pulmonary disease, low serum neutralizing antibody titers are associated with increased risk of hospitalization with RSV infection suggesting a vaccine may be beneficial. Although PIV infections are not commonly documented in older adults, several studies of community-acquired pneumonia and chronic obstructive pulmonary disease (COPD) exacerbations implicate PIV as a cause in 2-17% of cases (25, 26) .
cord-018785-tcr5xlf8	2018	The immunosuppressive therapy required to prevent organ rejection places the kidney transplant recipient at increased risk for donor-derived, nosocomial, and community-acquired infections as well as reactivation of latent pathogens. The immunosuppressive therapy required to prevent organ rejection places the kidney transplant recipient at increased risk for donor-derived, nosocomial, and community-acquired infections as well as reactivation of latent pathogens. The risk factors for development of CMV disease include donor seropositivity/recipient seronegativity(Dþ/RÀ), use of induction immunosuppression (antilymphocyte antibodies), donor age >60 years, simultaneous kidney-pancreas transplantation, treatment for acute rejection, impaired transplant function, and concurrent infection from other viruses (like EBV and HHV-6 and 7) (De Keyzer et al. The risk factors for PTLD include EBV naïve recipients who receive EBV seropositive organs, active primary EBV infection, younger recipient, coinfection by CMV and other viruses, prior splenectomy, second transplant, acute or chronic graft versus host disease, immunosuppressive drug regimen (OKT3 or polyclonal antilymphocyte antibody), and the type of organ transplanted.
cord-020010-q58x6xb0	2006	In the present study we reported the antiviral activity of neuraminidase inhibitor oseltamivir against lethal H5N1 influenza virus infection in ferrets, an appropriate animal model that closely resembles clinical signs of human influenza. Earl Kern 1 , Kathy Keith 2 , Robert Jordan 2 , Dennis Hruby 2 , Debra Quenelle 2 1 Department of Pediatrics, University of Alabama School of Medicine, Birmingham, AL, USA; 2 SIGA Technologies, Inc., Corvallis, OR, USA Although cidofovir (CDV) has been approved as an investigational new drug for emergency treatment of smallpox, its lack of oral activity and dose limiting toxicity dictates a need for continued development of better therapeutic agents for this potential bioterror disease. The in vitro antiviral activity of one of the most selective compounds, i.e. CHI-033, was assessed by (i) MTS-based cytopathic effect assays, (ii) virus yield reduction assays, (iii) real-time quantitative PCR (RT-QPCR) and (iv) by monitoring viral antigen expression.
cord-022380-49oti4zg	2009	Because infectious diseases may represent the most common cause of time lost from work, it is important for the clinician concerned with occupational medicine to understand the relationship of specific infections to specific work environments and practices, and to give at least as much attention to prevention as to diagnosis and treatment. Susceptible household contacts of infected adults and children pose a transmission risk in the workplace during the period of virus shedding, beginning about 10 days before the development of rash (about 1 week after exposure) until 7 days after rash appears. Varicella vaccination is also recommended for susceptible adolescents and adults who will have close contact with persons at high risk for serious complications of acquired varicella, including healthcare personnel and susceptible family contacts of immunocompromised individuals. The ACIP recommends that all healthcare personnel be immune to varicella, either from a reliable history of prior varicella infection or vaccination, to reduce the risk of infection and its complications, and to decrease the possibility of transmission of varicella zoster virus to patients (Table 22.
cord-022888-dnsdg04n	2009	Methods: Phospho-specific Western blot analyses were performed to verify the functionality of the different IFN-g pathway components, intra-and extracellular flow cytometry experiments were employed to determine the expression of antigen processing components and HLA class I cell surface antigens, quantitative real time-PCR experiments to confirm the absence of JAK2 and presence of pathway relevant molecules as well as, genomic PCR and chromosome typing technique to prove the deletion of JAK2. In order to accomplish these objectives we induced priming or tolerance of ovalbumin (OVA 323-339 peptide)-specific T cells from DO11.10 TCR transgenic mice in vitro or, following adoptive transfer of near physiologically relevant numbers of such cells into recipients, in vivo and correlated functional outcome (via proliferation and cytokine readout assays or antibody production) with E3 ubiquitin-protein ligases expression and the ubiquitination status of the TCR signalling machinery.
cord-023017-k6edtg58	2006	14/55 (25%) patients in AC who did not discontinue by week 24 received ribavirin dose reduction in comparison to 31/108 ( The clinical outcome in response to combination therapy for treatment of chronic hepatitis C virus (HCV) infection appears to be different for Caucasian versus African American patients. Over the period of combination therapy, most patients in which serum virus titers were reduced to non detectable levels had significant increases in T cell responses to HCV proteins. CHRONIC Background: Recent large prospective trials demonstrated that the combination therapy of interferon (1FN)-alphalribavirin significantly increased the ratio of a sustained virological response in patients with chronic hepatitis C in comparison with IFN monotherapy, especially in patients with high HCV-RNA titer and genotype lb. Results: Patients with chronic HCV infection showed higher MxA gene expression levels than healthy controls, indicating that hepatitis C virus induces IFN production.
cord-023033-tgt69ir6	2006	
cord-023346-8sqbqjm1	2005	• enhancement of automation/computerisation; • process control to provide an ''error-free pathway''; • (national) surveillance and trend analysis of results, preferably based on national working standards; • significantly increased sensitivity, especially from development of antigen/antibody ''combi'' assays (e.g. for HIV, and recently, for HCV); • awareness of HBsAg vaccine-escape mutants and design of assays to cope with this; • extension of range of agents and markers tested for (varies in different countries); • increasing range of assays available for testing donors with a relevant history of exposure to malaria or Chagas'' disease infection (for retrieval of otherwise wasted blood); • European Union''s in vitro diagnostics directive: this has caused some problems and reduced flexibility.
cord-023354-f2ciho6o	2005	• enhancement of automation/computerisation; • process control to provide an ''error-free pathway''; • (national) surveillance and trend analysis of results, preferably based on national working standards; • significantly increased sensitivity, especially from development of antigen/antibody ''combi'' assays (e.g. for HIV, and recently, for HCV); • awareness of HBsAg vaccine-escape mutants and design of assays to cope with this; • extension of range of agents and markers tested for (varies in different countries); • increasing range of assays available for testing donors with a relevant history of exposure to malaria or Chagas'' disease infection (for retrieval of otherwise wasted blood); • European Union''s in vitro diagnostics directive: this has caused some problems and reduced flexibility.
cord-023364-ut56gczm	2005	• enhancement of automation/computerisation; • process control to provide an ''error-free pathway''; • (national) surveillance and trend analysis of results, preferably based on national working standards; • significantly increased sensitivity, especially from development of antigen/antibody ''combi'' assays (e.g. for HIV, and recently, for HCV); • awareness of HBsAg vaccine-escape mutants and design of assays to cope with this; • extension of range of agents and markers tested for (varies in different countries); • increasing range of assays available for testing donors with a relevant history of exposure to malaria or Chagas'' disease infection (for retrieval of otherwise wasted blood); • European Union''s in vitro diagnostics directive: this has caused some problems and reduced flexibility.
cord-024003-698d15gk	2020	This study investigated the role of curcumin chitosan (CuCs) nanocomposite as a potential anti-HCV-4a agent in human hepatoma cells Huh7. 17, 19 Previously, chitosan nanoparticles (CsNPs) have been conjugated with antiretroviral agents like saquinavir, a protease inhibitor, to improve anti-HIV therapy; cell targeting efficiency increased by 92% compared to the soluble drug control. Antiviral activities of curcumin, CsNPs and CuCs nanocomposite were tested against the viral entry in infected Huh7 cells from positive HCV-4a patients through mixing of equal volumes of the nontoxic concentrations of the investigated materials and viral titer; in this assay one viral titer was involved (10 5 IU/mL). The HCV core protein expression level post-treatment of HCV infected Huh7 cells with curcumin, CsNPs, and CuCs nanocomposite against viral replication and entry was quantified in relation to β-actin as a control ( Table 7 , Figure 8 ).
cord-026112-58sa5z03	2020	This study aimed to investigate molecular epidemiology of HBV and HCV coinfection in Iranian HIV-infected individuals. Materials & methods: In this cross-sectional study, serological markers of HBV and HCV infection (hepatitis B surface antigen [HBsAg], hepatitis B e-antigen [HBeAg], hepatitis B e-antibody [HBeAb] and hepatitis B core antibody [HBcAb]) and anti-HCV antibodies [anti-HCV Abs] were tested in 198 Iranian HIV-infected patients. HIV/HBV-coinfected people have a higher rate of progression to liver fibrosis, cirrhosis, HCC, less clearance of HBsAg and occult HBV infections (OBI) are more frequent in these patients [13] . The aim for this study is to investigate the prevalence of HCV and/or HBV coinfection in Iranian HIV-infected individuals. According to a previous study, prevalence of cirrhosis in HIV/HBV/HCV triple-infected patients was higher than HIV/HBV-or HIV/HCV-coinfected individuals [57] .
cord-027860-s97hdhh6	2020	Although common upper respiratory bacterial pathogens, such as Moraxella (Branhamella) catarrhalis, Streptococcus pneumoniae, and Haemophilus influenzae, may be isolated from patients with acute bronchitis, their relevance is questionable because these bacteria can be present in the respiratory tract of healthy individuals. In the treatment of Bordetella pertussis, early administration of a macrolide antibiotic and patient isolation will likely decrease coughing paroxysms and limit spread of disease (Braman, 2006) (SOR: A). Risk factors for Pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent antibiotic therapy, health care-associated exposures or stay in hospital (especially in the ICU). Patients who present with severe infection or whose infection is progressing despite empiric antibiotic therapy should be treated more aggressively; the treatment strategy should be based on results of appropriate Gram stain, culture, and drug susceptibility analysis. For suspected MRSA skin infections, oral treatment options include trimethoprim-sulfamethoxazole, clindamycin, and doxycycline of purulent material when performing incision and drainage in the event that the patient fails to improve and antibiotic coverage becomes necessary.
cord-030361-0tepkjdl	2020	In a study conducted by Foster and colleagues, data was combined from nine phase 2 and phase 3 clinical trials to evaluate efficacy and safety outcomes in HCV patients ≥ 65 years old treated with the pan-genotypic regimen, glecaprevir/pibrentasvir, for 8, 12, or 16 weeks [28] . Shiffman and colleagues reported outcomes of 123 patients aged 65 years or older enrolled in three phase 3 studies who received sofosbuvir/velpatasvir, a pan-genotypic DAA, for 12 weeks for the treatment of chronic HCV [29] . Safety and efficacy of sofosbuvir/ velpatasvir for the treatment of chronic hepatitis C in patients aged 65 years or older: a retrospective analysis of phase 3 studies The efficacy and safety of direct acting antiviral treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection
cord-253768-y35m3vh1	2020	Nevertheless, a number of barriers to care in people who use drugs need to be addressed to end the opioid and HIV epidemics in the United States as well as reduce the other infectious disease health outcomes. To address these barriers we recommend expanding Medicaid, expanding access to harm reduction services, improving treatment and surveillance to enhance the continuum of care, and treating opioid and other substance use disorders (SUD), including through lowbarrier hospital and community-based treatment, as well as in the criminal justice setting. Increased state and federal funding are needed to expand SSP and other harm reduction services, including access to MOUD and infectious diseases treatment services in order to decrease HCV, HIV, IDU-related infections, and vaccine-preventable diseases, and improve OUD-related outcomes [26, 27] .
cord-253825-d9borky8	2014	ARB has been shown to display antiviral in vitro and/or in vivo activity against a number of enveloped or non-enveloped RNA or DNA viruses, including influenza viruses A, B and C , respiratory syncytial virus, SARS-CoV, adenovirus, parainfluenza type 5, poliovirus 1, rhinovirus 14, coxsackievirus B5, hantaan virus, Chikungunya virus, HBV and HCV [reviewed in Boriskin et al. Shi and coworkers showed a greater inhibitory effect on influenza A H1N1 when ARB was added before infection or when it was pre-incubated with the virus (Shi et al., 2007) , suggesting that membrane impregnation and/or metabolites could underlie ARB antiviral activity (see Section 6.). Recently, Tannock and coworkers reported a potent antiviral activity of ARB on several virus families responsible of respiratory infections in animals and humans, in particular on influenza A H3N2 (IC50 12 lM), and the non-enveloped Picornaviridae poliovirus 1 and rhinovirus 14 (Brooks et al., 2012 ; see also Brooks et al., 2004) .
cord-255781-55zrmgxq	2011	These agents consist of naturally occurring small proteins with molecular weights of 15,000 to 27,600 Da. 3 Each is considered a first-line option for the treatment of chronic hepatitis C virus (HCV) infection in combination with ribavirin. Along with the list of additional indications approved by the Food and Drug Administration shown in Table 1 , IFN-a was shown to be an effective treatment for the symptoms of an aggressive case of chronic active Epstein-Barr virus, but did not eliminate infection entirely. IFNs have been tested repeatedly against infectious diseases, but injections are used mostly for the treatment of viral hepatitis C and prevention of infections in patients with chronic granulomatous disease clinically. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection
cord-256036-gd53s4dv	2013	In contrast to human hepatocytes, murine cells do not support HCV entry thereby creating a first and important barrier for a broader host tropism of the virus. Utilizing blocking antibodies specific to CD81 or the viral envelope protein E2, expression of entry factor mutants and mice with a targeted disruption of the SCARB1 gene validated uptake of HCV into murine hepatocytes in an HCV glycoprotein-mediated fashion. Taking advantage of the high mutational plasticity of HCV, three adaptive mutations in the viral glycoproteins E1 and E2 were identified that allowed the virus to enter cells expressing human SCARB1, CLDN1, OCLN and mouse CD81. Recently, a genetically humanized mouse model was constructed utilizing cell culture produced recombinant hepatitis C virus to activate a cellular encoded reporter (Dorner et al., 2011, in press ). Human occludin is a hepatitis C virus entry factor required for infection of mouse cells A humanized mouse model to study Hepatitis C virus infection, immune response, and liver disease
cord-256118-gxhhwqdd	2020	
cord-256769-flfycl7i	2011	
cord-258234-qn8xp4v9	2014	Cyclophilin inhibitors that reduce viral replication also block interactions between cyclophilin A and NS5A, suggesting that this association is important during the viral life cycle and might be the relevant target of the antiviral activity of cyclosporine [11] [12] [13] . HCV NS5A is a protein that is rich in both proline residues and disorder and that associates with cyclophilin A via domain 2. However, these regions share several common properties: the flexible cyclophilin-interacting loop in CA is also bracketed by prolines, just as the PAWARPDYNP motif in HCV; residues 86, 91, and 96 that surround the glycine-proline in CA influence viral susceptibility to cyclophillin inhibitors similar to mutations surrounding NS5A P319 [25] ; and the critical glycine-proline is amino-terminal to regions of CA that are actually more proline rich and predicted by bioinformatics analysis to be disordered, analogous to the positioning of the PAWARPDYNP motif in HCV NS5A.
cord-259916-gr6v098c	2016	Like all positive-sense RNA viruses, hepatitis C virus (HCV) induces host membrane alterations for its replication termed the membranous web (MW). This review will summarize the recent studies that have led to our current knowledge of the role of viral and host factors in the biogenesis of the MWs and discuss how HCV uses this specialized membrane structure for its replication. A later study of cells containing a subgenomic HCV replicon reported that the membrane alterations induced by HCV replication consisted in part of double-membrane vesicles (DMVs; Figure 1 ) with a diameter around 200 nm that were also positive on immunoelectron microscopy with antibodies against NS5A and double-stranded RNA (dsRNA) [15] . [10] first showed that expression of viral nonstructural proteins resulted in membrane alterations that morphologically resemble those observed in replicon cells, demonstrating that viral RNA replication is not required for membranous web formation. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex
cord-260099-mthwab4p	2009	The present study suggests that LSECtin interaction with DC-SIGNR might contribute to HCV binding to liver sinusoidal endothelial cells. About a half of the DC-SIGNR-HEK293T cells were bound to the soluble Fc-LSECtin but not control-Fc protein, whereas only 6% of the mock cells were adhered to LSECtin (Fig. 1c) . Pre-incubation with the soluble LSECtin protein resulted in a dramatic decrease in the affinity of HCV E2 to the HEK293T-LSECtin cells (Fig. 3c) . Our present study suggests that LSECtin, a recently identified C-type lectin, could interact with DC-SIGNR and CD81 and was involved in HCV binding. previously reported that they could not detect the binding of HCV pseudotype particles to LSECtin expressed cells [14] , which is inconsistent with our results. In summary, the present study suggests that LSECtin interaction with DC-SIGNR might contribute to HCV binding to liver sinusoidal endothelial cells.
cord-261287-l4649du3	2004	However, a cumulative sustained virological response (SVR) was observed in only 22% (95% Confidence interval (CI), 14 -30%) of 111 patients enrolled in four pilot uncontrolled studies aiming to assess the efficacy and tolerability of ribavirin plus interferon alfa1 administered thrice weekly in HIV/HCV co-infected patients [4 -7] . In order to establish that the SVR in the triple therapy arm is at least three times higher than the 18% sustained response rate observed in HIV-co-infected patients treated with interferon and ribavirin in pilot studies [4] [5] [6] [7] , it was calculated that at least 64 patients should have been enrolled. In conclusion, intensification of interferon alpha schedule and amantadine addition do not appear to improve the limited efficacy of standard combination therapy including interferon thrice weekly plus ribavirin for the treatment of chronic hepatitis C in HIV-co-infected patients.
cord-263433-oldy0gta	2015	
cord-264326-teahway7	2020	According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than −8.00 kcal/mol and better prediction results than reference compounds. Since the 3D structure of the active site of the enzyme is crucial for catalytic activity, we proceeded to a comparison of the SARS-CoV-2 main protease, Mpro, with the HIV-1 protease, the HCV protease (NS3 protein) and the human proteases DPP-4, thrombin, Factor Xa, renin and ACE, which constitute known drug targets with approved inhibitors. The structural similarity between the SARS-CoV-2 protease and some of the selected proteases, in combination with the existence of the same amino acids at certain positions of the substrate cleavage site, such as Ser at the P1'' position of the recognition sequence of the HCV protease and thrombin are promising features in the effort to identify effective SARS-CoV-2 protease inhibitors among the approved drugs of the selected proteases.
cord-264713-38dlh3wg	2004	Viral load and antiviral resistance or subtyping assays are now part of the biological monitoring of patients chronically infected by human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and CMV. The most striking illustration of the power of molecular techniques concerns blood transmitted viruses-human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) for which spectacular progresses in the detection and treatment of viral diseases have been made following the introduction of qualitative and quantitative nucleic acid tests (NAT). For example, we have observed, using a DNA-microarray assay (see below), that the analytical sensitivity of multiplex RT-PCR detection of six viruses, i.e. influenza A, influenza B, RSV A/B, parainfluenza 1, 2 and 3 is reduced by a factor of <1-2 logs compared to single detections, depending on the virus.
cord-264936-3posyr5n	2014	RESULTS: The codon-optimized gene had an increased adaptation index value (from 0.65 to 0.85) and reduced GC content (from 62.62 to 51.05) in tobacco and removed the possible deleterious effect of "GGTAAG" splice site in native HCVcp. Blotting assays via specific antibodies confirmed the expression of the 15 kDa HCVcp. The expression level of HCVcp was enhanced by 4-5 times in P19 co-agroinfiltrated plants with better outcomes for PVX, compared to pBI121 vector (0.022% versus 0.019% of the total soluble protein). In this study, we aimed to: i) Construct an efficient transient tobacco expression system for HCVcp N-121 by designing a highly codon-optimized gene and employment of the Iranian Jafarabadi-tobacco plant cultivar which is a high biomass producer ii) Evaluate the expression level of HCVcp for a potato virus X-based vector (PVX) (32) com-pared to a classic pBI121 binary plant vector in co-agroinfiltration with P19 gene silencing suppressor plasmid and iii) Assess the antigenicity of this tobacco-derived HCVcp for potential clinical (diagnostic and vaccine formulation) applications.
cord-265005-e6rpryrh	2014	We will discuss the expression patterns and functions of endosomal TLRs with regards to IFN production in uninfected specialized immune cell types, pDCs and XCR1 + DCs. Plasmacytoid DCs uniquely produce very large amounts of IFNs in response to in vitro stimulation with many viruses, without being infected (46) . Under these conditions, to promote health over disease, the benefits for the host of producing high circulating levels of IFNs in order to induce widespread cell-intrinsic anti-viral defenses might prevail over the deleterious effects that this could cause on certain cell types or tissues. Subcapsular sinus macrophages rapidly become infected by viruses incoming from the lymph and produce large amounts of IFNs. This altruistic suicide prevents virus dissemination to other adjacent cell types and promotes the induction of innate and adaptive anti-viral immunity (87) .
cord-265588-1tcaleeo	2018	title: Phytochemical profiling and antiviral activity of Ajuga bracteosa, Ajuga parviflora, Berberis lycium and Citrus lemon against Hepatitis C Virus Therefore, this study was designed to find out phytochemicals and investigate antiviral activity of methanol extract of Ajuga bracteosa, Ajuga parviflora, Berberis lycium and Citrus lemon against Hepatitis C Virus (HCV infection). Antiviral activity of the selected plant extract was find out against HCV infected HepG2 cells. Phytochemical analysis showed the presence of flavonoids and phenols in all plant extracts while amino acids, alkaloids and tannins were present in B. So, it was important to find out the toxic effects of four medicinal plants used in the current study before evaluating for anti-HCV activities. Antiviral activities of methanol extract of four medicinal plants were tested against HCV and results has been summarized in Fig. 2 for 24 h and Fig. 3 for 48 h treatments.
cord-265592-r8nlef0h	2001	
cord-267867-q52nvn0n	2016	Several siRNAs dramatically reduced or even abrogated the replication of selectable subgenomic HCV replicons upon cotransfection of human hepatoma cells with viral target and siRNAs, or upon transfection of cells supporting autonomous replication of HCV replicon with siRNAs. Importantly, three siRNAs also proved capable of strongly inhibiting virus production in cell culture. Several siRNAs dramatically reduced or even abrogated the replication of selectable subgenomic HCV replicons upon cotransfection of human hepatoma cells with viral target and siRNAs, or upon transfection of cells supporting autonomous replication of HCV replicon with siRNAs. Importantly, three siRNAs also proved capable of strongly inhibiting virus production in cell culture. We sought to determine whether the siRNAs si240-1a, si244, and si313, shown to be the most efficient in inhibiting the replication of HCV subgenomic replicons both transiently and under selective pressure, are also capable of efficiently blocking virus infection in cell culture.
cord-268467-btfz6ye8	1989	The 3′-noncoding region of the genome contains an 11-nucleotide sequence, which is relatively conserved throughout the Coronavirus family and lends support to the theory that this region is important for the replication of negative-strand RNA. This result suggested that the HCV229E subgenomic mRNAs possess a nested-set structure similar to other coronaviruses and that A34 represented a cDNA clone of either the 3''-end of the genomic RNA or the leader sequence. The 3''-noncoding region contains the sequence TGGAAGAGCCA, 75 nucleotides from the 3''-end (Fig. 4) which is relatively conserved among coronaviruses and is found at approximately the same location in all of these viral genomes (Kapke and Brian, 1986; Skinner and Siddell, 1984; Armstrong et a/., 1983; Lapps et al., 1987; Kamahora et a/., 1988; Boursnell et al., 1985) ( Table 1) . Three intergenic regions of coronavirus mouse hepatitis virus strain A59 genome RNA contain a common nucleotide sequence that is homologous to the 3''end of the viral mRNA leader sequence
cord-269194-b1wlr3t7	2015	
cord-269294-vx7xr80t	2005	
cord-270498-hh6h50t2	2017	Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. In this study, our data revealed that celastrol significantly inhibits HCV replication, and that the anti-HCV effect of celastrol was attenuated by the HO-1 specific inhibitor tin mesoporphyrin (SnMP) or HO-1 gene expression silencing. Celastrol-mediated HO-1 induction contributed to the anti-HCV action through inducing antiviral IFN response and inhibiting HCV NS3 protease activity. As shown in Fig. 7B , HO-1 RNA expression levels were induced by celastrol compared with non-celastrol treated cells and the JNK inhibitor SP600125 significantly reduced the HO-1 inductive effect of celastrol. In the present study, we found that a natural product celastrol could effectively inhibit HCV NS3/4A protease activity and enhance IFN-mediated antiviral gene expression through HO-1 induction (Figs.
cord-271091-ffn59sgf	2007	
cord-271635-tydlyc1q	2018	
cord-273555-i1d4quos	2014	Authors'' reply SIRS, We thank Dr Galmozzi and Dr Lampertico for their comment on our recently published paper on the effect of the dinucleotide frameshift variant in ss469415590 in the interferon (IFN)-k4 gene on interferon/ribavirin treatment and its relationship with the two commonly used single nucleotide polymorphisms (SNP) in IL28B (rs12979860, rs8099917). 1, 2 We agree that our study does not provide insights on the causal relationship between IFNL4 and treatment response in patients with chronic hepatitis C virus (HCV) infection. We would like to remind them that up-regulation of intrahepatic interferon-stimulated genes (ISG) is associated with treatment failure in patients with chronic HCV, and levels of ISG are differently distributed according to different IL28B genotypes. 1 reported a randomised controlled trial comparing oral (100 mg twice daily ferrous sulphate for 3 months) or intravenous (1000 mg ferric carboxymaltose, single-dose infusion) iron supplementation and placebo for anaemia after nonvariceal upper gastrointestinal (GI) bleeding.
cord-274080-884x48on	2018	For the majority of animal viruses, the activation of these fusion or penetration mechanisms occurs through conformational changes and structural rearrangements in viral surface proteins and/or the whole virion shell that may destabilize the capsid core. D: Three mechanisms (I.-III.) of DNA viruses replication are shown: (I): Following entry and uncoating, the DNA genome is transported to the nucleus; products of early genes (regulatory proteins, transcription factors) regulate the synthesis of viral enzymes (e.g. DNA polymerase) required for genome replication; expression of late genes encoding structural capsid proteins in the cytosol, they are then transported into nucleus where packaging and pre-assembly take place; preassembled procapsids exit the nucleus and leave the cell (e.g. Herpesviruses). Here, we provide an overview of in vitro methods, including cell-based assays, that may be suitable for screening of antivirotics that interfere with the key steps of viral life cycles and target either virus or cell-encoded proteins required for the infectivity.
cord-276364-zyw5aukk	2019	
cord-279202-iyteg4h9	2008	title: Expression of alternate reading frame protein (F1) of hepatitis C virus in Escherichia coli and detection of antibodies for F1 in Indian patients Apart from the core (21 kD), a novel hepatitis C virus (HCV) frame shift protein (F1) is synthesized from the initiation codon of the polyprotein sequence followed by ribosomal frame shift into the −2/+1 reading frame. Further, results of western blots, carried out with patients sera titrated with purified core protein, confirmed the presence of antibodies specific to F1. The positive signal observed for F1 in western analysis with HCV infected sera suggests that F1 protein is synthesized in the natural course of HCV infection in Indian patients as well. Functional properties of a 16 kDa protein translated from an alternative open reading frame of the core encoding genomic region of hepatitis C virus
cord-280330-ibvbowl0	2013	While vaccine efforts have proven successful for preventing and eradicating some viral infections, many viruses cannot be targeted by immunization, including dengue virus (DENV), human cytomegalovirus (HCMV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV) [1] [2] [3] [4] [5] . We demonstrated that the two structurally-related compounds mediated their antiviral activities by targeting HSV-1 viral glycoproteins that interact with cell surface GAGs. Taking note of the fact that many viruses employ GAGs to initially bind to the host cell, and based on evidence that CHLA and PUG may act as GAG-competitors, we explored the antiviralpotential of these two tannins against a number of viruses known to interact with GAGs. Viral models included DENV, HCMV, HCV, MV, and RSV ( Table 1 ). We suggest that CHLA and PUG have potential as novel cost-effective and broad-spectrum antivirals for controlling emerging/recurring infections by viruses that engage host cell surface GAGs. Dulbecco''s modified Eagle''s medium (DMEM) and alpha minimal essential medium (AMEM) were purchased from GIBCO-Invitrogen (Carlsbad, CA, USA).
cord-280878-1kt51viz	2016	For other viroporins, these studies are still mostly in their infancy, although a highresolution structure of the hepatitis C virus (HCV) p7 protein has been recently described (Ouyang et al., 2013) that may be useful for the rational design of p7 channel inhibitors in the future. Structure and ion channel activity of the human respiratory syncytial virus (hRSV) small hydrophobic protein transmembrane domain The small hydrophobic protein of the human respiratory syncytial virus forms pentameric ion channels NMR structure and ion channel activity of the p7 protein from hepatitis C virus Influenza B virus BM2 protein has ion channel activity that conducts protons across membranes Identification of an ion channel activity of the Vpu transmembrane domain and its involvement in the regulation of virus release from HIV-1-infected cells Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus
cord-281389-sht0yx4a	2020	Examination of a publicly available gene expression data set (Gene Expression Omnibus [GEO] accession number GSE147507) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of A549 human lung cells also showed a significant upregulation of CD47 compared to mock-infected controls (Fig. 1D ). Multiple PBMC subsets showed significantly upregulated CD47 expression in response to Borrelia burgdorferi infection compared to naive cells (Fig. 1E) . Overall, the combined in vivo and in vitro results from multiple pathogen infections in both human and mouse cells indicated that the upregulation of CD47 was a conserved host response possibly related to host sensing mechanisms. Compared to healthy controls, monocytes and DCs from HCV patients demonstrated a sustained upregulation of CD47 at all treatment time points, including the 6-month posttreatment time point ( Fig. 3B (B) CD47 MFI on human total PBMCs from 4 separate donors stimulated with titrated concentrations of R848 from 0.1 g/ml to 10 g/ml, as indicated, for 48 h.
cord-281883-l9yshyc7	2009	
cord-281941-97t45w73	2012	
cord-284376-plwyjhl8	2020	All specimens tested negative by direct examination for PJ, whereas 27 were positive by real-time PCR (BAL, n = 18; sputa, n = 7, and TA, n = 2); Following stringent clinical, microbiological and imaging criteria ( Table 1 ) , PJP was deemed to be the most probable diagnosis in 12 episodes occurring in unique patients. In contrast, corticosteroid use within the month before sampling was not different between The probability of Pneumocystis jirovecii (PJ) pneumonia (PJP) for each patient was retrospectively evaluated by an expert committee including infectious diseases and microbiology specialists at both centers, on the basis of (i) documented PJ presence in respiratory specimens by microscopy; (ii) compatibility of clinical signs and symptoms (at least 2 of the following: subtle onset of progressive dyspnea, pyrexia, nonproductive cough, hypoxaemia and chest pain), (iii) compatible (suggestive) radiological findings (chest radiograph and/or high-resolution computed tomographic scan detection of interstitial opacities and/or diffuse infiltration infiltrates); (iv) complete resolution of symptoms after a full course of anti-PJP treatment; (v) absence of alternative diagnosis.
cord-284549-edliu3it	2019	
cord-284551-j0nooxmd	2013	
cord-284693-mgpxnnk0	2020	Advanced recipient age, diabetes mellitus, severe liver disease (Child Pugh >10), IL-28B polymorphism, high HCV RNA >10 7 IU/ml, ischemic/reperfusion injury, CMV, donor age >65 years, cold ischaemic time over 8 hours and warm ischemia over 90 minutes, marginal graft, DCD donor, higher immunosuppression in particular high dose corticosteroids for acute cellular rejection, use of anti-thymocyte globulin were significantly associated with rHCV in the liver allograft 15, 16 . Initial studies with sofosbuvir and ribavirin combination therapy for post-transplant rHCV showed poor drug tolerance, however, the main adverse event was anaemia related to ribavirin in 62% of patients, and subsequent hepatic decompensation related to the low haemoglobin 38 . A study by Pellicelli et al., showed significant adverse events including hepatic decompensation and 25% mortality in those with advanced disease following treatment with daclatasvir and sofosbuvir for post-transplant rHCV 51 .
cord-284904-qw1ig2v4	2009	In this study, we investigated the role of autophagy on hepatitis C virus (HCV) RNA replication and demonstrated anti-HCV effects of an autophagic proteolysis inhibitor, chloroquine. Inhibition of autophagy and replication of HCV replicon Cells were treated with 3-methyladenine (10 mM) or mixture of E64d (1 lg/ml) and pepstatin A (1 lg/ml), chloroquine (10 -7 -10 -3 M), interferon (IFN)a (100 U/ml) for 18 h, the levels of replication of HCV replicon were assessed by luciferase assay. To clarify the role of autophagy on the replication of HCV, Huh7/ Rep-Feo cells were treated with 3-methyladenine (10 mM) or a mixture of E64d (10 lg/ml) and pepstatin A (10 lg/ml) which inhibited autophagic protein degradation. Anti-HCV effect of chloroquine independent of IFN signaling pathway IFN-inducible double-stranded RNA-activated protein kinase R (PKR) plays a key antiviral role against hepatitis C virus [26, 27] .
cord-284978-vh1x6pg9	2013	Herein, we developed a multiplexed helicase assay based on graphene oxide (GO) for high-throughput screening of inhibitors of HCV NS3 helicase and severe acute respiratory syndrome coronavirus (SARS CoV) helicase. [10] Herein, we show that the GOHA can be used for measuring the activities of HCV NS3 helicase and SARS CoV helicase in a single mixed solution using two distinct DNA substrates tethered to different fluorophores, and furthermore, for multiplexed high-throughput screening to discover highly selective small-molecule inhibitors of these helicases ( Figure 1 ). A 96-well plate mGOHA was used to screen a 10 000 compound library to discover inhibitors of SARS CoV helicase and HCV NS3 helicase (Figure 3) . [17] Two compounds, antiHCV-Hel-2 and -3, showed a dose-dependent decrease in the Luc/MTT values with the respective half-maximal effective concentrations (EC 50 ) of 188.1 AE 32.6 and 56.8 AE 7.4 mm, indicating that they dose-dependently blocked HCV RNA replication in the cultured Huh-7 cells (Figure 5 b,c) .
cord-285505-8norumv6	2014	
cord-285868-fz5utxss	2014	In addition to regulation of cell death, it is reported that HCV induces the expression of CHOP at mRNA and protein levels and is correlated with autophagy induction; knockdown of CHOP not only increases HCV PAMP-mediated innate immune activation, but also elevates its inhibitory effect on virus replication (Ke and Chen, 2011) . Overexpression of HCV E1 and/or E2 induces the expression of CHOP in a PERK-dependent manner (Chan and Egan, 2005) ; while upon HCV infection, CHOP protein is upregulated by PERK, activating transcription factor (ATF6), and inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) collectively. It was reported that rotavirus NSP4 viroporin initiates autophagy to transport viral proteins to sites of virus replication for assembly of mature particles, which involves an increase of cytoplasmic calcium and subsequent activation of the CaMKK-β-AMPK pathway. Regulated IRE1-dependent decay pathway is activated during Japanese encephalitis virus-induced unfolded protein response and benefits viral replication
cord-286334-d9v5xtx7	2020	More detailed monitoring on how these physiological parameters change over time (perhaps including more complex cytokine studies), in these severely ill, influenza A(H1N1)pdm09-infected patients admitted to ICU-ECMO units, may eventually yield data to improve their management and clinical outcomes. 5 In the current study, we characterized a new HCV subtypes among chronic hepatitis C patients in Yunnan, China, initially designated as 6xi, further analyzed its evolutionary history and investigated its baseline RAS by next generation sequencing (NGS) method. The samples met the following inclusion criteria: (1) hepatitis C antibody-positive for 6 months with normal serum alanine aminotransferase (ALT) levels; (2) subject was residing in Yunnan province and was over 18 years old; (3) complete demographic information and clinical data were available; (4) consented to the use of patient information in studies on HCV epidemics; and (5) were treatment-naïve during sampling.
cord-286719-1xjmlwqr	2018	The developed AuNP-based detection techniques are reported for various groups of clinically relevant viruses with a special focus on the applied types of bio-AuNP hybrid structures, virus detection targets, and assay modalities and formats. These techniques represent the majority of molecular techniques applied in virus detection and include various types of target amplification techniques (e.g., PCR, loop-mediated isothermal amplification (LAMP), transcription-mediated amplification, and nucleic acid sequence-based amplification), signal amplification techniques (e.g., branched DNA and hybrid capture), and probe amplification techniques (e.g., ligase chain reaction and strand-displacement amplification). [70] developed an impedimetric electrochemical assay for the detection of AIV M gene sequences based on measuring changes in the impedimetric behavior of the electrode when the target DNA hybridizes with the capture DNA probes immobilized onto its surface and is subsequently labeled by AuNPs via streptavidin/ biotin interaction (Fig. 12C) .
cord-289321-ahl46ql9	2018	
cord-291321-ao80xk11	2015	Hepatitis C virus [8, 9] Enhanced fission and mitophagy Core, E1-E2 Activation of Drp-1, and mitochondrial translocation of Parkin Inhibition of apoptosis and innate immune response, facilitates persistent infection Pseudorabies virus [136] Fragmented mitochondria Glycoprotein B (GB) Altered functioning of Miro protein Affects intracellular calcium signaling and mitochondrial motility Human cytomegalovirus [130] Enhanced fission vMIA Affects mechanism of Bax Inhibition of apoptosis Epstein-Barr virus [128] Enhanced fission LMP2A Up regulation of Drp-1 Cell migration and apoptosis Hepatitis B virus [7] Enhanced fission and mitophagy HBx Parkin and PINK1 up-regulation and Drp-1 phosphorylation Inhibition of apoptosis and innate immune response, facilitates persistent infection Influenza A virus [98] Induction of mitophagy Unknown The NOD2 and RIPK2 promote ULK1 phosphorylation to induce mitophagy Inhibits inflammasome activation and reduces disease severity Influenza A virus [137, 138] Induction of mitochondrial fragmentation inhibition of mitochondrial β-oxidation of fatty acids [109] .
cord-292940-kg1rl6rb	2020	
cord-293646-d4qcckh1	2003	The first small molecule inhibitor of Hepatitis C Virus (HCV), the NS3 protease inhibitor BILN-2061, entered phase 2 clinical trials, producing a striking reduction in viral load in treated individuals. Inhibitors of Hepatitis B Virus (HBV) -Adefovir dipivoxil iHepsera''") (1) was approved in the US for the treatment of HBV on September 20'', 2002 and in the European Union on March 1 lth, 2003, providing a second small molecule antiviral to add to lamivudine (3TC) and the injectable protein IFNa as the only approved agents for treating HBV infection. Pyridinedicarboxamide S represents the first report of a non-nucleoside inhibitor of HBV reverse transcriptase enantiomer of q is active in cell culture and appears to prevent proper formation of the viral nucleocapsrd. A significant advance towards establishing a correlation between replicon inhibition and clinical efficacy was recently accomplished with the disclosure of preliminary clinical data for BILN-2061, a selective inhibitor of the NS3 serine protease of HCV that is structurally related to 13.
cord-293653-u2qrxq6t	2007	In addition to these cellular events, a number of reports demonstrated that CyP plays a critical role in the life cycle of viruses, especially human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The action of PPIases leads to changes in protein conformation (Takahashi, 1999) , but the binding of CsA and FK506 to CyP and FKBP, respectively, inhibits the activity of these enzymes (Fischer et al. The CsA/CyP or FK506/FKBP complex, subsequently interacts with and inhibits calcineurin (CN), a phosphatase involved in the activation of the transcription factor NF-AT. Members of the CyP family play roles in a variety of cellular processes including the immune response, transcription, mitochondrial function, cell death, and chemotaxis, as described below. However, the best-characterized role identified for CyPA is not in normal cellular physiology, but rather as co-factor during the human immunodefi ciency virus-1 (HIV-1) viral life cycle (See below).
cord-293790-7hyelm88	2010	title: Autophagy protein ATG5 interacts transiently with the hepatitis C virus RNA polymerase (NS5B) early during infection To identify novel cellular factors that may play an essential role in HCV RNA replication, we have previously screened a human liver cDNA library for proteins interacting with the HCV NS5B RNAdependent RNA polymerase (RdRp). Here we report that ATG5, a protein required for the formation of DMV in embryonic stem cell (Mizushima et al., 2001) , specifically interacts with HCV NS5B. As a control, a panel of proteins (RAR-β, RAR-α, HCV core, and nonstructural protein: NS3 prot , NS3 hel , NS4A, and NS4B) cloned in the GAL4 DNA binding domain was tested for interaction with ATG5. A. Soluble yeast extracts containing NS5BΔ21 (N-terminal c-myc tag) and ATG5 (N-terminal HA tag) were incubated with different monoclonal antibodies and the immunoprecipitates were pulled down using protein A/G beads.
cord-293857-o8rlqsq5	2015	Also, we will outline successful designs of organic carbamates, including a variety of cyclic ether-derived carbamates, as suitable amide bond surrogates leading to a wide range of novel organic carbamates as potent HIV-1 protease, βsecretase, serine protease, and cysteine protease inhibitors. 172−174 A number of FDA-approved HIV protease inhibitor drugs contain an important carbamate functionality. 179, 230 Further development of carbamate-derived novel HIV-1 protease inhibitors is shown in Figure 12 . This backbone binding strategy to combat drug resistance led to the development of a series of very potent carbamate-derived protease inhibitors. Carbamate derivative 281 (Figure 24 ), a diphenyl phosphonate ester containing a Cbz group and bearing a single amino acid side chain, showed very good inhibitory activity against human plasma kallikrein, useful for the treatment of hereditary angioedema. Design and synthesis of potent HIV-1 protease inhibitors incorporating hexahydrofuropyranol-derived high affinity P(2) ligands: structure-activity studies and biological evaluation
cord-294842-aesiff1f	2014	Three-dimensional reconstructions of the WNV KUN replication sites revealed an intimate association of the rough ER (rER) with the bounding membrane of the VPs [20] (Figure 2B ), resembling the vesicles observed in DENV-infected cells. In cells infected with TBEV, one of the most important tick-transmitted viruses in Europe and Asia, virus particles and membrane-connected vesicles were also observed inside the ER [25] , similar to what was described for DENV and WNV KUN . Importantly, pulse-radiolabeling experiments localized sites of active RNA replication to the outer surface of single-membrane tubules [71] and isolation of the membranous replication factories and their subsequent visualization by EM revealed that they form rosette-like structures composed of virus-induced cytoplasmic vesicles [124] . Formation of plant RNA virus replication complexes on membranes: Role of an endoplasmic reticulum-targeted viral protein
cord-298033-kzdp9edn	2019	Quasispecies dynamics in disease prevention and control following statement will be obvious to the reader: "If a single mutation is able to confer resistance to an antiviral agent, and the mutation does not cause a significant selective disadvantage to the virus (fitness decrease) in the considered environment, a drug-resistant virus mutant will be present in most, if not all, virus populations" (Domingo, 1989) . The phenotypic barrier to drug resistance is equivalent to the fitness cost inflicted upon the virus by the mutations and corresponding amino acid substitution(s) required for resistance [Fitness cost is treated in Chapter 4 (Section 4.6) and in Chapter 7 (Section 7.4.2) in connection with the frequency of monoclonal antibody-or cytotoxic T-cell-escape mutants in viral populations]. For viruses that replicate in cell culture, it is possible to estimate the minimal viral population size needed to select a drug-resistant mutant which is generally positively correlated with the genetic barrier ( Fig. 8.5 ).
cord-298736-9bvyp21d	2016	In the past decade mass spectrometry based proteomics methods have reached sensitivities and high throughput compatibilities of genomics methods and now allow the reliable quantitation of proteins in complex samples from limited material. Since then technological developments like antibody based affinity purification (AP), mass spectrometry (MS) of proteins, DNA mediated transformation and molecular cloning led to the discovery of dozens of receptors for human pathogenic viruses (Fig. 1) . While transcriptomics can reveal long-term alterations of the cellular state, virus entry usually occurs within minutes and typically relies on rapid changes of protein conformation, localization, interactions and post-translational modifications (PTM). Of note, high resolution proteomics can not only reveal transient interactions of VAP with enzymes, but also has the potential to identify proteolytic cleavage sites and redox modifications in VAPs. It is conceivable that virus induced protein interactions during entry not only serve to promote the virus uptake pathway, but can also help cloak viruses and lead to immune evasion.
cord-299719-bvdsz626	2013	Next, the development of cell-culture-grown hepatitis C virus (HCVcc) systems that can assemble and release of infectious viral particles has made it possible to the study structural regions using trans-complementation systems. A series of replicon RNAs carrying mutations (in the NS3, NS4B, NS5A and NS5B regions) that abolished replication were transfected into Huh-7 hepatoma cells harbouring autonomous replicating HCV helper RNAs. In this context, only NS5A mutations in the low complexity sequence I (LCS I) domain have been efficiently rescued ( Table 1 ). These results have clarified the role of Core, p7 and LDs in pseudo-infectious particle production and have indicated that some steps of virus assembly take place around LDs. Various trans-packaging systems have been developed with subgenomic replicons. Trans-encapsidation of hepatitis C virus subgenomic replicon RNA with viral structure proteins Naturally occurring hepatitis C virus subgenomic deletion mutants replicate efficiently in Huh-7 cells and are trans-packaged in vitro to generate infectious defective particles
cord-299747-qovrstak	2014	
cord-300154-3p7tjp5j	2011	Here we review the application of CARS microscopy for label-free imaging of cells and tissues using the natural vibrational contrast that arises from biomolecules like lipids as well as for imaging of exogenously added probes or drugs. Here we review the application of CARS microscopy for label-free imaging of cells and tissues using the natural vibrational contrast that arises from biomolecules like lipids as well as for imaging of exogenously added probes or drugs. High-resolution CARS microscopy combined with multimodal imaging has allowed for dynamic monitoring of cellular processes such as lipid metabolism and storage, the movement of organelles, adipogenesis and host-pathogen interactions and can also be used to track molecules within cells and tissues. High-resolution CARS microscopy combined with multimodal imaging has allowed for dynamic monitoring of cellular processes such as lipid metabolism and storage, the movement of organelles, adipogenesis and host-pathogen interactions and can also be used to track molecules within cells and tissues.
cord-300642-c7adeis1	2006	
cord-302295-nblmshni	2013	TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Recombinant human activated protein C (rhAPC, Xigris®, Eli Lilly), the only drug specifically registered for sepsis, has recently been withdrawn from the market following the negative results from the PROWESS-SHOCK study that did not show reduction in mortality at 28 or 90 days in patients with septic shock (4) . The discovery of TLRs and their involvement in innate immune responses has attracted much interest into the development of drugs for controlling infections and improving sepsis management. Moreover, upon infection, innate immune cells will likely sense several MAMPs via several TLRs and non-TLR PRRs. For example, Gram-negative bacteria express MAMPs that may trigger redundant inflammatory pathways through TLR2 (lipopeptides), TLR4 (LPS), TLR5 (flagellin), TLR7 (ssRNA), and TLR9 (bacterial DNA).
cord-303189-ktl4jw8v	2015	Acting in both autocrine and paracrine manner, IFN interferes with viral replication by inducing hundreds of different IFN-stimulated genes with both direct anti-pathogenic as well as immunomodulatory activities, therefore functioning as a bridge between innate and adaptive immunity. In these cells, the HCV-induced miR-21 has been recently reported to be involved in evasion of IFN-I production and stimulation of HCV replication, upon suppression of MyD88 and IRAK1 expression, that is required for the TLR7-mediated sensing of the virus [100] . Amongst RNA viruses that, as HCV, can establish a persistent infection, HIV-1, a lentivirus from the Retroviridae family, represents a paradigm for its ability to prevent or circumvent the innate immune response mediated by IFN-I. Overall, viruses as HCV and HIV-1 have evolved nifty strategies to dampen the host innate response in cells where a productive infection may take place, while they induce infection-independent mechanisms in non-permissive cells to facilitate the viral life cycle and promote a chronic inflammation.
cord-305039-grsv06j7	2013	As for HIV, mAbs directed against spike viral proteins, as well as against host receptors, may act at an early stage of infection by preventing the binding of the virus on the cell surface. In some chronic viral infections, virus-specific immune cells may persist in a ''non-functional'' state, because of an imbalance of immunoregulatory signals involving multiple inhibitory and activating receptors, triggered by soluble factors and/or cell surface ligands. Therapeutic approaches using specific mAbs to block host immunosuppressive molecules (antagonism) or to trigger activating receptors (agonism) may be a valid strategy to restore immune cell function and treat various chronic viral infections. In a proof-of-concept passive immunization trial with humans, it has been demonstrated that a cocktail of the three broadly neutralizing mAbs -2G12, 4E10 and 2F5was able to delay viral rebound in patients whose infections were fully suppressed by antiretroviral treatment before administration of the antibodies [76] .
cord-305085-bv7udg9k	2011	Postnatal exposure of susceptible infants to CMV, including premature infants without passively acquired maternal antibodies against CMV, infants born to CMV-seronegative mothers, and immunodeficient infants, can cause significant clinical illness (pneumonitis, hepatitis, thrombocytopenia).* In one study of premature infants followed up to 12 months, Vochem et al 430 found CMV transmission in 17 of 29 infants (59%) exposed to CMV virolactia and breastfed compared with no infants infected of 27 exposed to breast milk without CMV. 38, 104, 121 Laboratory reports demonstrate the presence of cell-free virus and cell-associated virus in breast milk as well as various immunologic factors that could block or limit infection.* A dose-response relationship has been observed, correlating the HIV viral load in human milk as well as a mother'' s plasma viral load with an increased transmission risk for the breastfed infant. 76 No case of transmission of yellow fever virus from an infected mother to her infant via breastfeeding or breast milk has been reported.
cord-305263-fgwf6wy3	2012	IFN therapy therefore has the advantage over DAA treatments in that, in addition to stimulating genes that block viral replication in infected cells, IFNs activate other innate and adaptive immune responses to combat the virus. For example, polymorphisms in host genes encoding proteins associated with regulation of an IFN response such as interferon receptor a-chain (IFNAR1) [10] , the IFN-inducible myxovirus resistance GTPase protein, Mx [11] , the IFN-inducible 2 0 ,5 0 -oligoadenylate synthetase (OAS) [12] and the suppressor of cytokine signaling (SOCS) 3 associated with regulation of an IFN response [13] , are predictive markers linked with the rate of sustained virological response (SVR) to HCV infection following IFN-a treatment. Remarkably, distinct highly pathogenic respiratory viruses, namely influenza viruses and the SARS-CoV, encode nonstructural proteins in their genomes that function as virulence factors that specifically target the host innate IFN response, further emphasizing the importance of IFNs as broad-spectrum antivirals.
cord-305303-82n96ukr	2012	As shown in Figure 2 , similar numbers of surviving colonies were observed when the cells were transfected with the plasmids encoding mCherry-NS3 activated MazF or the red fluorescent protein alone, suggesting that expression of NS3-activable ribonuclease in naïve HEK293 T-REx cells (that do not express NS3) cause minimal toxicity, if any. The ER membrane-targeted zymoxin colocalizes with NS3 protease in vivo Previously we described a HEK293 cell line which inducibly expresses (by addition of tetracycline) a fusion between EGFP and the coding sequence of the full length NS3 (including the helicase domain) followed by NS4A from HCV 1a genotype [10] . When infection reached ,50% (about 50% of the cultured cells showed expression of the HCV-core protein, as detected by immuno-staining and fluorescence microscopy), the mixed culture and a culture of uninfected cells were treated with NS3 activated MazF or uncleavable-MazF encoding adenoviruses at MOI of ,3.
cord-305393-96mrxt8a	2011	Recombinant 1b hepatitis C virus polymerase was found to enhance TLR3 signaling in the lung epithelial BEAS-2B cells when added to the media along with either poly(I:C) or viral dsRNAs. The polymerase from the genotype 2a JFH-1 HCV was a poor enhancer of TLR3 signaling until it was mutated to favor a conformation that could bind better to a partially duplexed RNA. These results demonstrate that several viral RNA-binding proteins can enhance the dsRNA-dependent innate immune response initiated by TLR3. Transfection of two plasmids, one containing an interferon stimulated response element (ISRE) promoter-driven firefly luciferase and a second encoding a constitutively expressed Renilla luciferase allow the analysis of TLR3 activation by different RNAs. HEK 293T cells expressing WT TLR3 responded to poly(I:C) (1-2 mg/ml), better than viral dsRNAs (1-2 mg/ml) purified from Reovirus and BPEV (Fig. 1B) .
cord-306934-29ljbl7g	2009	Finally, molecular modeling investigations indicated that compounds of structure A–C, active against BVDV, could work targeting the viral RNA-dependent RNA-polymerase (RdRp), having been observed a good agreement between the trends of the estimated IC50 and the experimental EC50 values. First of all, the binding site identified by our procedure is very close to the putative binding site proposed for two allosteric inhibitors of BVDV RdRp, VP32947 and BPIP, 23 Table 5 Cytotoxicity against MT-4, MDBK, BHK and Vero-76 cell lines and YFV, Reo-1, CVB-2, RSV, HSV-1 and Sb-1 inhibitory activity of triazene derivatives of structure F and G Tables 3 and 4. In view of these considerations, molecular modeling investigations were performed to study wether the active compounds of structures A-C could target the BVDV RNA-dependent RNA-polymerase (RdRp), which shares some structural similarity with HCV RdRp. Indeed a good agreement was observed between the trend exhibited by the IC 50 (calculated from the estimated free energies of binding) and the corresponding biological activities determined for these compounds in BVDV infected MDBK cell line.
cord-307556-k2lavvca	2013	Herein, we developed a multiplexed helicase assay based on graphene oxide (GO) for high-throughput screening of inhibitors of HCV NS3 helicase and severe acute respiratory syndrome coronavirus (SARS CoV) helicase. [10] Herein, we show that the GOHA can be used for measuring the activities of HCV NS3 helicase and SARS CoV helicase in a single mixed solution using two distinct DNA substrates tethered to different fluorophores, and furthermore, for multiplexed high-throughput screening to discover highly selective small-molecule inhibitors of these helicases ( Figure 1 ). A 96-well plate mGOHA was used to screen a 10 000 compound library to discover inhibitors of SARS CoV helicase and HCV NS3 helicase (Figure 3) . [17] Two compounds, antiHCV-Hel-2 and -3, showed a dose-dependent decrease in the Luc/MTT values with the respective half-maximal effective concentrations (EC 50 ) of 188.1 AE 32.6 and 56.8 AE 7.4 mm, indicating that they dose-dependently blocked HCV RNA replication in the cultured Huh-7 cells (Figure 5 b,c) .
cord-307817-2vy28i4m	2014	The prevalence of chronic viral infectious diseases, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza virus; the emergence and re-emergence of new viral infections, such as picornaviruses and coronaviruses; and, particularly, resistance to currently used antiviral drugs have led to increased demand for new antiviral strategies and reagents. Based on the complex structure of the PA C-terminal domain (PA C ) and the first 25 amino acids of PB1 [99] , a subset of modifications on N-terminal peptide of PB1 was shown to diminish the binding affinity of PA and PB1, inhibit polymerase activity, and attenuate the replication of influenza virus [100] [101] [102] . Because both the polymerase complex and NP show significant conservation between different influenza viruses, these results demonstrated that targeting the formation of viral RNP is a valid approach to the development of small molecule therapies against serious antiviral resistance to currently available drugs, such as adamantanes or neuraminidase inhibitors.
cord-307934-84zfabti	2014	Further studies by cofractionation analysis and immunoelectron microscopy of the released particles showed that NS5A-Core complexes, but not NS4B, were present in the low-density fractions, but not in the high-density fractions, of the HCV RNA-containing virions and associated with the internal virion core. Overall, our results suggest that HCV NS5A is associated with the core of the low-density virus particles which exit the cell through a preexisting endosome/exosome pathway and may contribute to HCV natural infection. Both NS5A and Core proteins are found to be closely associated with and co-transported along the microtubules from the perinuclear region of cells via the LDs and endosomes to the plasma membrane. (A) The HCV-infected cells (at day 10 p.i.) were labeled with antibodies specific for Core protein (red) and NS5A (green) (upper row) or NS4B (green) (lower row).
cord-311823-85wj08gr	2008	In this section, we review recent studies in which genomic approaches have been used to provide new information on how viruses trigger and regulate innate immune pathways, and to evaluate the use of type I IFN-based therapy as a means to enhance the innate immune response to HCV. In RIg-I-deficient cells, influenza virus fails to elicit the expression of IFNβ and of many ISgs, including key antiviral mediators such as IRF3, STAT1 (signal transducer and activator of transcription 1), IFIT1 (IFN-induced protein with tetratricopeptide repeats 1; also known as ISg56) and ISg54 (also known as IFIT2). Although these studies have provided considerable information regarding the genes activated downstream of TlR activation, it will be advantageous to extend genomic analyses in the context of viral infection using cells lacking the expression of specific TlRs. The ability of a virus to establish an infection depends, at least to some extent, on its ability to block the host innate immune response or to modulate the activity of antiviral effector proteins.
cord-312080-pu6m4qad	2016	This review focuses on the recent progress of human virological research with 3D cell culture models, including human viral growth, replication, proliferation, infection, viral life cycle, virus-host interaction and the development of antiviral drugs. A multitude of research has shown that RWV-derived models utilizing human cells are a valuable tool for investigating viral growth, replication, viral infection, viral entry, the viability of virions and virus-host interaction (Margolis et al., 1997; Long et al., 1998; Nickerson et al., 2007; Straub et al., 2007; Barrila et al., 2010; Berto et al., 2013; Goodwin et al., 2015) . As keratinocytes are the main target cells for productive infection in vivo for VZV, characterization of viral replication in organotypic raft cultures of these cells represents a very relevant model for studying virus-host cell interactions and antiviral agents (Andrei et al., 2005) .
cord-314148-5xisw9au	2005	Several reports have analyzed the extent of infections in various populations in America and Europe by estimates of HCV antibodies in sera from patients and volunteers [Bradburne and Somerset, 1972; Candeias et al, 1970; Cavallaro and Monto, 1970 ; Hamre and Beem, 1972; Hendley et al, 1972; Hovi et al, 1979 ; Kaye et al, 1971; McIntosh et al, 1970; Zakstelskaya et al, 19721 . In this study representative viruses from the 229E and OC43 antigenic groups were used in ELISA to measure the antibodies to these viruses in sera collected during the winter from patients and volunteers from the Basrah area of Southern Iraq. 67 random sera were collected from healthy adult volunteers at the Common Cold Unit, Salisbury, before inoculation with any viruses, and tested by ELISA for antibodies to HCV 229E and CV Paris.
cord-314254-9ye8tfvz	2014	To date, there is no evidence for an animal reservoir of viruses closely related to hepatitis C virus which may have crossed the species barrier to cause disease in humans and resulted in the current pandemic. Recently, several studies discovered new viruses related to hepatitis C virus, belonging to the hepaciand pegivirus genera, in small wild mammals (rodents and bats) and domesticated animals which live in close contact with humans (dogs and horses). Non-primate hepaciviruses (NPHV) were initially discovered in domestic dogs and subsequently in horses 12, 13 and other diverse and widespread HCV-like viruses have been reported in wild populations of rodents and bats. Furthermore, liver function analyses revealed no indication for hepatic inflammation as c-glutamyl transferase and glutamate dehydrogenase values were within reference range, with the exception of a mildly elevated c-glutamyl transferase New HCV-like viruses in different mammalian hosts Pfaender et al 4 level in one horse.
cord-314567-purplsjn	2018	HCV-core associated proteins are implicated in RNA processing and RNA virus infection as well as in functions previously shown to be altered in Hepatitis C virus core expressing CD4 + T cells, such as cell cycle delay, decreased proliferation, and induction of a regulatory phenotype. HCV-core associated proteins are implicated in RNA processing and RNA virus infection as well as in functions previously shown to be altered in Hepatitis C virus core expressing CD4 + T cells, such as cell cycle delay, decreased proliferation, and induction of a regulatory phenotype. As studies using the whole virus do not allow for the elucidation of the specific molecular mechanisms in which each protein is implicated, in this work, we focused on a single viral protein, showing that in CD4 + T cells, HCV core protein mostly localizes in the nucleus and specifically in the nucleolus where it is greatly enriched.
cord-314753-xflhxb13	2017	The percentage of reads mapping to RNA virus genomes in the rRNA-depleted BBV Panel samples was between 40 and 150-fold higher than in corresponding untreated controls. The depth plots in Fig. 3 again show unbiased and even coverages across both genomes, and the percentages of reads mapping to viral targets was again much higher in the rRNA-depleted sample than in the untreated comparator (61-fold and 85-fold for HCV and HPgV respectively). By depleting host-derived nucleic acids and making modifications to an existing library preparation protocol to account for ultra-low RNA input quantities, we have been able to reconstruct effectively full-length genomes of HCV, HEV and HIV from plasma samples with viral loads of 10 4 IU/ml (copies/ml for HIV) and substantial fractions of complete genomes at 10 3 IU/ml. Additionally, our system was able to recover viral sequences from a panel of diverse RNA viruses diluted in human plasma, with a broad correlation between the genomic coverage and depth metrics and approximate concentration.
cord-316703-8kxx3034	2012	The aim of this study was to investigate whether the NS3/4A serine protease of CHV specifically cleaves human mitochondrial antiviral signaling protein (MAVS) and Toll-IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF). The target specificity for the MAVS and TRIF cleavage sites was tested by coexpressing them with CHV or HCV NS3/4A protease constructs. coli cells coexpressing the lambda cI repressor with either MAVS or TRIF cleavage site and a CHV NS3/4A construct, lambda phage replicated up to 2,000-fold more efficiently than in cells expressing a CHV protease variant that included a substitution in catalytic residue S139 ( Fig. 3A and 3B). In this study, we tested the ability of CHV NS3/4A protease to specifically cleave the human adaptor proteins MAVS and TRIF. Canine orthologs of human MAVS and TRIF differ in sequence at the cleavage site processed by HCV NS3/4A protease; therefore, they were not tested in this study.
cord-316968-rowoylge	2006	Maximum likelihood (ML) method with codon-substitution models is a powerful statistic tool for detecting amino acid sites under positive selection and adaptive evolution. We analyzed the hepatitis C virus (HCV) envelope protein-coding sequences from 18 general geno/subtypes worldwide, and found 4 amino acid sites under positive selection. The purpose of this study is therefore to use the ML method [9] to infer adaptive evolution and positively selected amino acid sites of HCV envelope protein entire coding sequences containing all 6 HCV genotypes. We took HCV envelope glycoprotein as an example to explore the adaptive evolution driven by immune environment pressure of coding sequences of 27 HCV containing 18 geno/subtypes and found that a number of amino acid sites were under positive selection and ML could be employed for identifying the adaptive evolution of RNA virus on a large scale of genetic diversity.
cord-317595-siwzjeea	2018	Herein, we apply an evolutionary approach to shed light into HCV origin, to analyze its adaptation to human populations, and to verify if the emergence of drug-resistant variants is a result of positive selection. We used Single-Likelihood Ancestor Counting (SLAC) and fixed effects likelihood (FEL) (Kosakovsky Pond and Frost, 2005) to calculate the rates of nonsynonymous and synonymous changes at each site in the structural and in the non-structural region alignments (analyses were performed on alignments split on the basis of the recombination breakpoint detected by GARD). The observation that the positively selected sites are involved in HCV binding and infectivity suggests that hepaciviruses contributed to shape the genetic diversity of CD81 in bats. Using an evolutionary model that accounts for variation in the pressure of natural selection across sites and branches, we show that the common ancestor of extant HCV genotypes existed at least 3000 years ago, with a lower bound estimate of ∼5200 years before present.
cord-318853-mxyxwkhx	2005	Perhaps more importantly, ineluctable generation of broad phenotypic diversity after viral RNA is translated to protein quasispecies suggests a mechanism of disease that specifically targets, and functionally disrupts, the host cell surface molecules – including hormone, lipid, cell signalling or neurotransmitter receptors – that viruses co-opt for cell entry. Hence, as relative concentrations of wild-type and variant viral proteins vary, alteration of both processivity and fidelity of RNA pol results, permitting viruses to adaptively respond to environmental changes, including immune recognition and reaction to evolving cell receptors. As clear evidence exists for viral disruption of leptin function [106] and virus-associated weight gain in humans [107] and monkeys [108] , is it possible the global epidemics of type II diabetes mellitus, insulin resistance, hyperlipidaemia and obesity now prevalent [109] [110] [111] [112] [113] [114] [115] [116] , are just that; epidemics fundamentally caused by viruses that co-opt insulin or leptin or other associated receptors for cell access and generate protein quasispecies that disrupt receptor function?
cord-319754-5isw53wl	2020	Some viruses may use different entry mechanisms, this feature being likely dependent upon the membrane lipid composition of the host cell they infect as well as the particular cell surface factor attachment used. The question regarding whether the lipid-raft domains may serve as platforms to concentrate the proteins required for viral entry and, even though some evidence exists, to activate signaling pathways inside the host cell still remains unsolved. More recently, a Ca 2+ -dependent pathway of infection by the Rubella virus (RuV, Rubivirus family, Togaviridae) was demonstrated to proceed through direct binding of the fusion loop in the viral E1 protein to SM/cholesterol-enriched membranes [49] . More recently, a Ca 2+ -dependent pathway of infection by the Rubella virus (RuV, Rubivirus family, Togaviridae) was demonstrated to proceed through direct binding of the fusion loop in the viral E1 protein to SM/cholesterol-enriched membranes [49] .
cord-321053-lgae22f8	2013	Numerous in vitro studies in combination with a growing number of HCV sequencing data from patients undergoing DAA treatment underline that the virus can develop drug-resistance and fitness restoring compensatory mutations [11] . An emerging third group of antivirals, so called hosttargeting antivirals (HTA), may be part of such future combination therapies, in particular as HTAs hold the promise of overcoming some of the caveats of DAAs. HTAs are antibodies, RNAs or small molecules, which interfere with host factors needed for HCV propagation. On the one hand, this demonstrates that HCV can in theory evade HTA therapy by mutating the viral binding partner of the targeted host factor and in fact suggests a low genetic barrier to resistance. Targeting HCV RNA Replication: Phosphatidylinositol 4-kinase III alpha (PI4KIIIα) Genome wide RNA interference screens and in depth cell culture replication assays with HCV replicons and full length infectious virus have revealed numerous additional host dependency factors, that could in principle serve as antiviral targets [99] [100] [101] [102] [103] [104] [105] [106] [107] .
cord-321230-b5a1z14w	2020	Lastly, if an underlying cause of death code was recorded as ICD-10 R99 (other ill-defined and unspecified causes, usually assigned when cause of death is still under investigation), and manner of death was listed as "pending," "accident," or "undetermined," we re-categorized the death as drug-related if the death met the following criteria: attributable to a person aged 20 to 64 years who also injects drugs (defined as any drug-related diagnoses, use of injection drugs, record of opioid agonist therapy dispensation or injection related infection using physician diagnostic and billing data, hospitalizations, prescription data, vital statistics and emergency room data), based on validation studies in the US and in the BC-HTC (Centers for Disease Control and Prevention, 2004; to mitigate the impact of missing data on the analysis. We compared PLHCV and HCV-negative individuals who died of DRDs, estimated annual age and sex-adjusted drug-related mortality rates per 100,000 person-years (PY) for these groups and examined trends over time by sex.
cord-321505-m40s6uw9	2007	Background and Aim: We have reported previously that synthetic small interfering RNA (siRNA) and DNA‐based siRNA expression vectors efficiently and specifically suppress hepatitis C virus (HCV) replication in vitro. Intravenous delivery of the adenovirus expressing shRNA into transgenic mice that can be induced to express HCV structural proteins by the Cre/loxP switching system resulted in specific suppression of virus protein synthesis in the liver. Here, we report that HCV replication was suppressed in vitro by recombinant retrovirus and adenovirus vectors expressing short hairpin RNA (shRNA) and that the delivery of the adenovirus vector to mice in vivo specifically inhibited viral protein synthesis in the liver. These results indicated that the decrease in luciferase activities was due to specific suppressive effects of shRNA on expression of HCV genomic RNA and the viral proteins, and not due to non-specific effects caused by the delivery of shRNA or to toxicity of the adenovirus vectors.
cord-321773-5fw9abzl	2018	
cord-323963-whv88ggl	2006	Among RNA templates, hepatitis C virus (HCV) represents an excellent example to challenge the potential of LRP technology due to its extensive secondary structures and its difficulty to be readily cultured in vitro. Thus, our LRP protocol could be applied for the amplification of other difficult RNA templates and may facilitate RNA virus research such as linked viral mutations and reverse genetics. In some experiments, we mixed a RT enzyme with Pfu DNA polymerase (Stratagene), a similar strategy as used in long PCR, to improve full-length cDNA synthesis [8] . A representative neighbor-joining (NJ) tree constructed based on HCV E1 domain of 20 clones derived from 9.1 kb LRP product, which was amplified using mixed serum from samples LIV19 and LIV23. A refined long RT-PCR technique to amplify complete viral RNA genome sequences from clinical samples: Application to a novel hepatitis C virus variant of genotype 6
cord-324054-d71rj29o	1992	Abstract The complete nucleotide sequences of the hemagglutinin/esterase (HE) genes of human coronavirus (HCV) strain OC43 and bovine respiratory coronavirus (BRCV) strain G95 were determined from single-stranded cDNA fragments generated by reverse transcription of virus-specific mRNAs and amplified by polymerase chain reaction. Phylogenetic analysis suggests that the HE genes of coronaviruses and influenza C virus have a common ancestral origin, and that bovine coronaviruses and HCV-OC43 are closely related. We report here the complete nucleotide sequence of the HE genes of HCV-OC43 and BRCV-G95, and their phylogenetic relatedness to BCVs, MHV, and ICV. The predicted amino acid sequences of the HE genes from HCV-OC43 and BRCV-G95 (Fig. l) , BCVMost importantly, the putative acetylesterase active site (F-G-D-S) (at amino acids 72 to 75 in Fig. 2) is conserved in all HE proteins of human, bovine, and murine coronaviruses and ICV.
cord-324984-ojrpsdt9	2020	In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. 3 Altogether, targeting host factors is a very promising strategy with possibility to address the critical challenges faced with the DAAs. In this review, we summarize the recent advances made in HTAs from a medicinal chemistry standpoint, and the host targets are generally classified into three different categories based on the development stage of their corresponding inhibitors/modulators, namely the ones which reached Food and Drug Administration (FDA) approval, that have entered clinical trials and those in preclinical studies.
cord-325989-nf6ouaq3	2012	The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies. In the near future, targeting specific regulators of PRR-mediated innate response to withdraw viral subversion mechanisms, and access to novel surrogate measurable effector markers, hold the promise of new panviral therapeutics that will minimize adverse effects associated with type I IFN therapy.
cord-326217-ji0njeha	2018	We found that both inhibition of GSK3 function by synthetic inhibitors as well as silencing of GSK3β gene expression resulted in a decrease of HCV replication and infectious particle production, whereas silencing of the GSK3α isoform had no relevant effect on the HCV life cycle. To assess whether both GSK3 isoforms are required for HCV replication, we silenced GSK3α and / or GSK3β gene expression by transfecting siRNAs and quantified HCV RNA in Huh-7.5 cells harboring HCV subgenomic replicon (Con1) or infectious HCV (Jc1). Given the well-known dependency of HCV on miR-122 (Jopling et al., 2005 (Jopling et al., , 2008 Machlin et al., 2011) and the regulatory circuit between insulin-like growth factor 1 receptor, GSK3β, and miR-122 identified previously (Zeng et al., 2010) , we assessed the effect of GSK3 inhibition on miR-122 expression in Huh-7.5 cells harboring a subgenomic HCV replicon.
cord-327135-4c2flue4	2016	Interferon (IFN) lambda (IFN-λ or type III IFN) gene polymorphisms were discovered in the year 2009 to have a strong association with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection in human hosts. Three independent groups conducted genome-wide association studies (GWASs) involving treatment response to chronic hepatitis C virus (HCV) infections, in three different geographical regions of the world, and reported that single-nucleotide polymorphisms (SNPs) in the IFNL locus (Figure 1 ), had strong association with treatment-induced HCV clearance irrespective of ethnicity and geographical location of the hosts. 49 In stark contrast, a dominant model of inheritance (of the non-beneficial IFNL SNP minor allele) has consistently given the best explanation on the observed phenotypes in association studies with both spontaneous clearance and IFN-based treatment response in chronic HCV infections.
cord-330110-pamxy4av	2011	Interestingly, apparent binding affinities between lipids and tryptophan residues are comparable with those of Arb IC50 of the hepatitis C virus (HCV) membrane fusion. By combining surface plasmon resonance, fluorescence and NMR spectroscopy approaches, we showed that Arb directly interacts with the phospholipid membrane interface, with an affinity in the micromolar range, comparable to the concentration inhibiting HCVpp membrane fusion by 50% (IC50). Altogether our results demonstrate that Arb interacts with the polar head of phospholipid membranes and protein motifs enriched in aromatic residues, suggesting that the inhibitory activity of Arb on HCV entry and fusion could involve both types of interactions. Conversely, Arb inhibition of HCVpp membrane fusion, as assessed by a in vitro model system where the only proteins present are the viral glycoproteins, could merely reflect the interaction of Arb on lipids and/or on motifs present in HCV glycoproteins of any genotype.
cord-332422-s15o0hie	2011	HCV envelope glycoproteins are key determinants of HCV entry with a role in receptor binding and in mediating the fusion process between the viral envelope and an endosomal host cell membrane. Furthermore, functional non-infectious and capsidless structures, called subviral particles, can be produced when the HCV envelope glycoproteins are expressed alone in lipoprotein producing cell lines [8] , supporting the idea that HCV envelope glycoproteins play an active role during the budding process. The role of SRB1 in HCV entry was first suggested by its ability to mediate soluble E2 binding [13] and it was later confirmed by the inhibition of HCV infection with anti-SRB1 antibodies and by silencing of the protein in hepatoma cells (reviewed in [5, 26, 27] ). Virus-associated lipoproteins are likely playing a role in the early phase of HCV entry, whereas envelope glycoproteins are believed to take the lead after this initial step.
cord-332747-u46xryoo	2018	To determine which aspects of the HCV replication cycle are limited by lipin1 silencing, single cycle infection experiments were conducted by inoculating control and lipin1-deficient cell cultures at MOI 10 with genotype 2a D183 virus. Once cultures reached >95% of HCV-positive cells, they were transduced with lentiviral vectors expressing control, HCV RNA-targeting or LPIN1-specific shRNAs. At day 7 post-transduction, cells were split and samples of the cells and supernatants were collected 24 hours later to determine infectious virus production rate by infectivity titration HCV (C) and RNA levels by RT-qPCR (D). This reduced abundance is illustrated by a significant reduction in the fraction of cells displaying vesicular structures in lipin1-deficient cell cultures (Fig 7H) despite comparable transfection efficiency and viral protein expression levels, indicating that lipin1 may be required in a critical step leading to formation of the HCV-induced vesicular compartment.
cord-333331-ddcz7zck	2011	An improved, sensitive, specific, and rapid one-step reverse transcription loop-mediated isothermal amplification (LAMP) assay targeting the 5′ untranslated region (UTR) was developed to detect hepatitis C virus (HCV) infection. A variety of molecular diagnostic assays, such as reverse transcriptase PCR [12] , nucleic-acid-sequence-based amplification [13] , transcription-mediated amplification [29] , branched-chain DNA assay [26] , and in-house realtime PCR [8] , have been developed for the detection of HCV RNA. Confirmed cases of HCV infection were verified by a positive result in an enzyme-linked immunosorbent assay (Kehua Bio-engineering, Shanghai, China) for antibodies against HCV or a quantitative real-time PCR for HCV RNA. Given that the sensitivity of the AP-LAMP assay for detecting HCV is higher than that of the pre-LAMP method, the pathway of AP-based amplification was investigated. Reverse transcription-loop-mediated isothermal amplification assay for rapid detection of hepatitis E virus
cord-334493-rt7gqiev	2007	On the basis of our previous study on antiviral agents against the severe acute respiratory syndrome (SARS) coronavirus, a series of nucleoside analogues whose 5′-hydroxyl groups are masked by various protective groups such as carboxylate, sulfonate, and ether were synthesized and evaluated to develop novel anti-hepatitis C virus (HCV) agents. Since the 5′-O-unmasked analogue (i.e., 6-chloropurine-2′-deoxyriboside) was not sufficiently potent (EC(50) = 47.2 μM), masking of the 5′-hydroxyl group seems to be an effective method for the development of anti-HCV agents. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane, To a stirred solution of 31 (200 mg, 0.56 mmol) in dioxane (1 mL) was added 50% dimethylamine-water solution (8 mL) at room temperature, and the mixture was stirred overnight at the same temperature.
cord-335085-7pxkhgbq	2009	Material and methods ‐ Spinal fluids from 37 patients with AMON and 15 surgical control patients with protrusion of the intervertebral disk were assayed with a nested multiplex polymerase chain reaction with primers specific for human coronaviruses strain (HCV) 229E and OC43. To investigate the possibility of an infection with human coronaviruses (HCV) in early MS and as a possible cause of AMON we have analyzed cerebrospinal fluid (CSF) from patients with AMON using reverse transcriptase reaction and the polymerase chain reaction (RT-PCR) applying primers specific for HCV. CSF from 4 patients and 1 control ( Table 2) were positive on nested RT-PCR using the HCV-229E primers and all samples were negative with the HCV-OC43 primers. HCV-229E RNA was found in the CSF by RT-PCR in 4 of 37 patients with AMON and in 1 of 15 controls.
cord-337285-t6qr41wc	2007	Using cell culture systems, several cellular proteins have been identified as effective molecules for HCV RNA replication (Table 1) . [66] reported that lovastatin (LOV), one of the HMG-CoA reductase inhibitors, inhibited HCV RNA replication in HCV replicon-harboring cells. Depletion of the GGPP by statins may inhibit the geranylgeranylation of cellular proteins such as FBL2 and cause the anti-HCV effect in the cells. During the development of IFN therapy for patients with CH-C, the lack of a robust method of HCV RNA replication in cell culture has hampered research into the HCV life cycle and the discovery of potent new anti-HCV reagents. VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells Selectable subgenomic and genome-length dicistronic RNAs derived from an infectious molecular clone of the HCV-N strain of hepatitis C virus replicate efficiently in cultured Huh7 cells
cord-340220-raqapqg0	2013	We took advantage of these permissive cells expressing mCD81 and the previously described MT81/MT81w monoclonal antibodies (mAbs) (Silvie et al., 2006) to analyse the role of tetraspanin web-associated CD81 in HCV infection. Interestingly, as shown for one representative cell clone, cells expressing EWI-2wint exhibited a stronger staining with MT81w, indicating that EWI-2wint modifies CD81 membrane organization, probably by increasing the association of CD81 with the tetraspanin web. To strengthen the hypothesis that EWI-2wint induces a change in CD81 organization at the plasma membrane, we next analysed the membrane dynamics and partitioning of human CD81 (hCD81) molecules in Huh-7 cells expressing or lacking EWI-2wint by single-molecule fluorescence microscopy, which is a method of choice to characterize the diffusion of proteins and lipids in different regions of the plasma membrane (Owen et al., 2009 ). D. Huh-7w7/mCD81 clones expressing pcDNA3.1, EWI-2 or EWI-2wint were stained with MT81 and MT81w mAbs followed by PE-labelled secondary antibody and analysed by flow cytometry.
cord-341071-nwrl1qws	2020	Pharmaceuticals 2020, 13 Elucidating the function of each RNA domain and their modus operandi would provide an excellent scenario to address the control of infections caused by RNA viruses, broadening beyond proteins the repertoire of potential target candidates to fight viral diseases. Elucidating the function of each RNA domain and their modus operandi would provide an excellent scenario to address the control of infections caused by RNA viruses, broadening beyond proteins the repertoire of potential target candidates to fight viral diseases. Consequently, in contrast to other nucleic acid based strategies (ribozymes, antisense oligonucleotides, siRNA, among others), aptamers are postulated as excellent candidates to directly interfere with the functioning of essential structural domains of viral RNA genomes. Herein, we present an extension of a video we communicated at the 5th ECMC describing two examples of selection and characterization of aptamers targeting essential structural domains of respective viral RNA genomes, performed in our laboratory [21] .
cord-342676-ykog278j	2016	To identify the regions of the viral genome involved in this process, we used SELEX (systematic evolution of ligands by exponential enrichment) to identify RNA aptamers which bind specifically to Core in vitro. Comparison of these aptamers to multiple HCV genomes revealed the presence of a conserved terminal loop motif within short RNA stem-loop structures. We wished to investigate the possibility that similar specific secondary structures are present within HCV RNAs destined for packaging, and whether their interactions with Core cooperatively drive the RNA encapsidation and nucleocapsid assembly processes. A mutant genome unable to form such structures displays impaired viral infectivity whilst RNA replication is unaffected, indicating these motifs may interact specifically with Core. Role of RNA structures in genome terminal sequences of the hepatitis C virus for replication and assembly
cord-342901-ca2xxkb2	2015	Though PTB was the first, a wide spectrum of factors, largely nuclear RBPs, have also been proposed as poliovirus ITAFs, including Lupus autoantigen (La) (Meerovitch et al., 1993 (Meerovitch et al., , 1989 , poly(rC)binding proteins (PCBPs) (Blyn et al., 1996; Gamarnik and Andino, 1997) , upstream of N-ras (UNR) (Anderson et al., 2007; Boussadia et al., 2003; Hunt et al., 1999) , SRp20 (Bedard et al., 2007) and glycyl-tRNA synthetase (GARS) (Andreev et al., 2012) (Table 1 ). In addition, certain ITAFs play crucial roles in regulating the conversion of translation-competent genomic RNAs into replicationcompetent RNAs. PTB was known as a nuclear splicing factor when its role as an ITAF of poliovirus and EMCV was discovered; a classic hijacked nuclear protein pressed into a new role required for the virus.
cord-343902-hzh3cjzh	2013	Initial reports of CsA inhibiting HIV-1 surfaced in 1988, 25 although the first report specifically implicating CypA involvement in the HIV-1 life cycle was published five years later when it was reported that endogenous CypA colocalizes with the HIV-1 Gag protein in the cytoplasm, binding specifically to a Pro-rich sequence in the HIV-1 capsid domain of Gag. 26 X-ray crystallography later revealed that residues 85-93 of HIV-1 capsid bind to the active site of CypA, 27 and subsequent studies have shown that virions produced in the presence of Gag mutated in the CypA binding region, or under pressure from competitive CypA inhibitors, were less infectious than wild type virions. 36 Further support for CypA being the primary Cyp involved in HCV RNA replication include a demonstration that the catalytic PPIase activity of CypA is required for efficient HCV RNA replication, and the finding that a specific binding between CypA and NS5A is dissociable by addition of CsAbased Cyp inhibitors.
cord-343963-99rd3o79	2014	13, 14 Upon infection by viruses such as HCV, viral RNA is first sensed by cellular pattern recognition receptors (PRRs), and the PRR-mediated recruitment of adaptor proteins and the activation of downstream signaling lead to IFN production. First, we briefly discuss the signaling triggered by the retinoic acid-inducible gene 1-like receptor (RLR) and the Toll-like receptor (TLR), which leads to type I IFN synthesis and IFN-mediated signaling pathway activation, resulting in the expression of a variety of effector ISGs. We also summarize the strategies that HCV uses to escape IFN antiviral surveillance. 156 demonstrated that HCVinduced SG formation is IFN-and PKR-dependent and is inversely correlated with the induction of ISG proteins, such as myxovirus resistance gene A (MxA) and Ub-like (UBL)specific protease 18 (USP18), in HCV-infected cells without affecting the mRNA levels of these ISGs. Furthermore, the SG proteins TIA-1, TIAR and G3BP1 have been shown to play a critical role in HCV replication and infectious virus production.
cord-344084-z4t2wkgk	2020	The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. In agreement with studies showing that CCR5Δ32 homozygous genotype is a risk factor for symptomatic WNV infection in humans, Ccr5-/-WNV-infected mice showed a reduced capacity of viral control, increased disease severity, impaired leukocyte trafficking towards the brain, and high mortality rates than Ccr5 wild-type mice. In conclusion, although tissue analysis and evidence obtained in vitro suggest that the CCR5 is potentially involved in the pathogenesis of HPV, most studies point to a lack of involvement of CCR5Δ32 in susceptibility to HPV infection or HPV-associated diseases.
cord-345898-a6vt8kso	2016	There are three types of cell-based reporter systems that express certain reporter protein for positive-sense single strand RNA virus infections. An RVP is a type of virus-like particle (VLP) composed of viral structural proteins and a self-replicating replicon RNA containing a reporter gene [17, 63] . However, when the cells were infected with the specific virus, the viral RdRp was provided by the virus and the defective replicon was activated, resulting in high-level expression of the reporter gene, which could be easily examined [44] . However, when the cells were infected with the specific virus, the viral RdRp was provided by the virus and the defective replicon was activated, resulting in high-level expression of the reporter gene, which could be easily examined [44] . Development of Dengue type-2 virus replicons expressing GFP reporter gene in study of viral RNA replication
cord-347319-lcuma3eh	2011	HCV has two envelop proteins named as E1 and E2 which play an important role in cell entry through two main pathways: direct fusion at the plasma membrane and receptor-mediated endocytosis. To investigate the antiviral effect of LA (Chloroquine and NH(4)Cl) on pH dependent endocytosis, HCV pseudoparticles (HCVpp) of 1a and 3a genotype were produced and used to infect liver cells. For antiviral screening of Chloroquine and NH(4)Cl, liver cells were infected with HCVpp of 3a and 1a genotype in the presence or absence of different concentrations of Chloroquine and NH4Cl and there luciferase activity was determined by using a luminometer. We therefore tested the infectivity of HCVpp after treatment of target cells with different concentrations of Chloroquine and NH 4 Cl. HCVpp of 1a and 3a genotype demonstrated dose-dependent inhibition in the presence of Chloroquine and NH 4 Cl. Chloroquine and NH 4 Cl showed greater than 50% reduction of virus infectivity at 50 μM and 10 mM concentration respectively, suggesting a pH-sensitive route of virus entry (Figure 2a and 2b ).
cord-347710-ff64y6ef	2020	hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. 6, 13 It is well known that Hsp90 not only interacts and contributes to RNA polymerase assembly and nuclear import of some (−) ssRNA viruses (e.g., PB2 of influenza virus), but plays crucial roles in the folding process of viral capsid proteins and virion assemblies as well. 17, 18 As a critical component of cellular protein surveillance, the ATP-dependent molecular chaperone protects cells from damage caused by stress and takes part in a number of folding processes, including folding of newly synthesized polypeptides, recognition and refolding of misfolded or aggregated proteins, solubilization or degradation of proteins, transporting proteins, assembly or disassembly of oligomeric protein complexes, and the regulation of certain natively folded proteins.
cord-347992-coby2m6e	2010	Although ribozymes and DNAzymes have been extensively assayed as potential therapeutic agents, and different clinical trials have already tested their efficiency against various diseases [49] [50] [51] [52] , very few reports have described the direct application of in vitro selection strategies in the development of potentially therapeutic catalytic nucleic acids. Molecular studies have shown that this aptamer binds to the cell surface protein nucleolin and inhibits the activity of NF-KB, a ubiquitous transcription factor, through intracellular complex formation [108] . In a different approach, SELEX has been performed with the E2F1 protein to find in vitro selected RNA aptamers that bind to and inhibit E2F activity. Astier-Gi''s group described the characterization of two DNA aptamers (27v and 127v) that specifically bind to hepatitis C virus (HCV) RNA polymerase (NS5B), inhibiting its activity in vitro [146] . In vitro selection procedures for identifying DNA and RNA aptamers targeted to nucleic acids and proteins
cord-349358-leicos9j	2006	During the past few years, it has been demonstrated that RNAi, induced by specifically designed double‐stranded RNA (dsRNA) molecules, can silence gene expression of human viral pathogens both in acute and chronic viral infections. Likewise, expression vectors of siRNAs specific for two different regions of the WNV genome protected 293T cells from WNV infection, and significantly reduced viral RNA replication and virus production [35] . From the reports on the use of siRNA against human viral pathogens causing acute disease, we could learn that for each specific pathogen infecting a specific cell lineage or tissue, we would probably need to perform an indepth assessment, with proper in vitro and in vivo models, and develop specific delivery systems. The most challenging part of RNAi approaches for chronic viral infections is to design the best delivery method that would facilitate the targeting of the specific organ/cells with the appropriate expression system, for durable intracellular levels of gene-silencing effect.
cord-350571-6tapkjb6	2017	Possible solutions might be to use shared communication tools like Internet based communication programs and to introduce the patient as a participant at the IMRs. Please specify your abstract type: Research abstract Background and objective: International good pharmacy practice guidelines describe how pharmacists should counsel the patients about their medicines, offer additional services where needed, and intervene at drug related problems. Please specify your abstract type: Descriptive abstract (for projects) Background and objective: In order to improve the medication reconciliation and to implement training programs for the medical team in an associated to general hospital nursing (ASNH) home we measured the discrepancies between pharmacy registered treatments (PRT) and medical prescriptions (MP), and we analysed potentially inappropriate prescriptions according to ''''American Geriatrics Society 2015 Beers Criteria'''' and ''''STOPP-START 2014 criteria.
cord-350600-73q8mve4	2005	A method is described for the detection of human coronavirus 229E (HCV 229E) in nasal washings using RNA:RNA filter hybridization. In this paper we describe a specific and sensitive test to detect one of these major groups, HCV 2293, in nasal washings. Briefly, using a method based on that of Gubler and Hoffmann [19831, cDNAs were generated from HCV 2293 RNA isolated from infected C16 cells [Phillpotts, 19831. The results of virus titration and probing of nasal washings from seven volunteers are presented in Table I . Three of the seven volunteers suffered a cold, and all three volunteers had detectable coronavirus RNA in their nasal washings. The results we have obtained show that the detection of HCV 2293 infection by nucleic acid hybridisation is a reliable and specific method. Hybridisation to known quantities of HCV 2293 RNA showed that less than 1 ng of virus-specific RNA from C16 cells infected with HCV 2293 could be detected.
cord-350640-sz6xj5o3	2012	When transfecting our infectious firefly luciferase reporter virus genome Luc-Jc1 [14] into highly permissive Huh-7.5 human hepatoma cells [15] cultured in the presence or absence of serum, we measured comparable levels of luciferase activity 4 to 48 h after transfection ( Figure S1A ). Among the inhibitors tested, U0126 a selective inhibitor of the MAPK/ERK pathway, substantially decreased the production of infectious virus particles as is evident from the dose-dependent reduction of luciferase activity in the inoculated cells ( Figure 1B) . To investigate if PLA2G4A activity is relevant for the production of infectious HCV particles we treated Luc-Jc1 transfected cells with pyrrolidine-2 (Py-2), a specific inhibitor of this type of phospholipase [22, 23] . Irrespective of culturing these cells in the presence or absence of serum, we observed a strong and dose-dependent inhibition of production of infectious particles resulting in a more than 100-fold reduction of luciferase transduction at 5 and 20 mM of Py-2, respectively ( Figure 2B ).
cord-351365-dc9t3vh3	2016	Consequently, the onset of RBV treatment in chronically HEV-infected individuals can result in two divergent outcomes: viral extinction versus selection of fitness-enhanced viruses. Following an overview of RNA viruses treated with RBV in clinics and a summary of the different antiviral modes of action of this drug, we focus on the mutagenic effect of RBV on HEV intrahost populations, and how HEV is able to overcome lethal mutagenesis. Figure 1 provides an overview of a selection of RNA viruses against which RBV was shown to be active: hepatitis C virus (HCV, Flaviviridae), dengue virus (DENV, Flaviviridae), respiratory syncytial virus (RSV, Paramyxoviridae), influenza A and B virus (Orthomyxoviridae), chikungunya virus (CHIKV, Togaviridae), poliovirus (Picornaviridae), Hantaan virus (Bunyaviridae), and Lassa virus (Arenaviridae) [28, 29] ( Figure 1 ). Furthermore, mechanisms on the virus itself were described by inhibition of the capping efficiency, the viral polymerase, and a mutagenic effect on newly synthesized RNA genomes. A Mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with ribavirin treatment failure in organ transplant recipients