key: cord-295191-xu26mvc3
authors: Avirutnan, Panisadee; Mehlhop, Erin; Diamond, Michael S.
title: Complement and its role in protection and pathogenesis of flavivirus infections
date: 2008-12-30
journal: Vaccine
DOI: 10.1016/j.vaccine.2008.11.061
sha: 
doc_id: 295191
cord_uid: xu26mvc3

The complement system is a family of serum and cell surface proteins that recognize pathogen-associated molecular patterns, altered-self ligands, and immune complexes. Activation of the complement cascade triggers several antiviral functions including pathogen opsonization and/or lysis, and priming of adaptive immune responses. In this review, we will examine the role of complement activation in protection and/or pathogenesis against infection by Flaviviruses, with an emphasis on experiments with West Nile and Dengue viruses.

The complement system is comprised of soluble and cell surface associated proteins that recognize exogenous, altered, or potentially harmful endogenous ligands [1] . Complement is activated through three distinct pathways referred to as the classical, lectin, and alternative pathways depending on specific recognition molecules [1, 2] . Classical pathway activity is triggered by C1q binding to antigen-antibody complexes on the surface of pathogens or by spontaneous tickover [3] . The lectin pathway is initiated by mannan binding lectin (MBL) or ficolin recognition of carbohydrate structures on the surface of microbes or apoptotic cells. The alternative pathway is constitutively active at low levels through the spontaneous hydrolysis of C3 and also serves to amplify activation of the classical and lectin pathways. Despite the distinct triggering mechanisms, the classical, lectin, and alternative pathways generate convertase enzymes (C4bC2a for classical and lectin, and C3bBb for the alternative) which cleave C3, the central component of the complement system, and expose a reactive internal thioester bond on C3b necessary for covalent attachment to target surfaces. The binding of C3b back to C4b2a and C3bBb C3 convertases forms the classical and alternative pathway C5 convertases, respectively. These enzymes cleave C5 and promote assembly of C5b-9 membrane attack complex (MAC), which lyses pathogens or infected cells. Sub-lytic amounts of C5b-9 on a cell surface can activate granulocytes and endothelial cells, whereas soluble C5b-9 independently induces inflammation through cytokine induction [4] [5] [6] [7] [8] [9] [10] . The release of anaphylatoxins (C3a and C5a) by the C3 and C5 convertases also contributes to the host inflammatory response by promoting chemotaxis of immune cells via the interaction with specific G-protein coupled transmembrane receptors (C3aR and C5aR) [11] . Deposition of opsonic C3 and C4 fragments (C3b and C4b) on a pathogen facilitates binding and phagocytosis by complement receptors (CR1, CR3, CR4, and CRIg), a process called opsonization, which helps to clear microbial infections [12, 13] .

To limit inappropriate activation and potential tissue damage, the complement system is controlled by a group of cell surface and soluble regulators [14] . Negative regulation of complement activation is achieved by several independent mechanisms: (a) proteolytic cleavage of C3b and C4b by the plasma serine protease factor I in conjunction with one of the membrane or plasma cofactors (membrane cofactor protein (MCP or CD46), complement receptor 1 (CR1 or CD35), factor H, and C4 binding protein (C4BP) [15] [16] [17] [18] ; (b) dissociation of the C3 and C5 convertases, a process known as decay accelerating activity, which involves decay accelerating factor (DAF or CD55), CR1, C4BP and factor H [19] [20] [21] [22] [23] ; (c) MAC formation is inhibited by the membrane regulator CD59 (protectin) [24, 25] , the soluble regulator apolipoprotein clusterin (Apo-j) [26] [27] [28] [29] [30] , and vitronectin [31, 32] ; (d) specific protease inhibitors (e.g., serpins and C1 inhibitor) limit cleavage of C4 and C2 by dissociating the classical (C1r-C1s) and lectin (MBL-associated serine protease 2 (MASP-2)) pathway serine proteases [33] .

Beyond its roles in direct recognition and clearance of microbes, complement activation is critical for generating an efficient adaptive immune response. Ligation of complement receptors enhances humoral immune responses [34, 35] . Binding of the complement split products C3d, C3dg, or iC3b [36] by CR2 (CD21) lowers the threshold for B cell activation by cross-linking the B cell receptor with the CD19/CD81/CR2 co-receptor complex [37] . Indeed, conjugation of C3d to viral glycoproteins increases their immunogenicity up to 10,000 fold [38] [39] [40] [41] , and C3 −/− or CR2 −/− mice have impaired humoral responses to T cell-dependent (TD) antigens [42] [43] [44] [45] . Additionally, expression of CR2 on follicular dendritic cells (DC) is required for B cell survival within the germinal center, affinity maturation, and the establishment of B cell memory [46] [47] [48] . In addition, CR1 (CD35), a type I integral membrane protein that binds C3b, C4b, and C1q, and MBL, also plays a role in establishment of B cell responses [49] [50] [51] . This glycoprotein is expressed on all peripheral blood cells in humans with the exception of platelets, natural killer cells and most T cells [49, 52] . In primates, CR1 expression on erythrocytes contributes to immune complex clearance and transfer of C3b-opsonized antigens to splenic and hepatic macrophages [53, 54] . In mice, CR1 is expressed as an alternative splice product of the Cr2 gene and is restricted to B cells and follicular dendritic cells [55] [56] [57] . Profound defects in humoral immunity have been observed in CR1/CR2 −/− mice [42, 43, 45, 58] , with little effect on T cell activity [59, 60] . CR1/CR2-mediated antigen trapping on follicular dendritic cells enhances antigen presentation to B cells, and is required for both primary and secondary humoral responses [61, 62] .

Complement and its receptors can also augment T cell activation. CR3 and CR4 can mediate phagocytosis of iC3b-opsonized antigens on antigen presenting cells, and thus, may augment antigen presentation. In the absence of complement C3, T cell responsiveness to influenza virus, lymphocytic choriomeningitis virus (LCMV), Leishmania, and alloantigens are reduced [59, 60, 63, 64] . Correspondingly, C3b opsonization augments protein antigen uptake [65, 66] and T cell stimulation [65, 67, 68] . Covalent C3b modification can target antigen to specific MHC class II containing vesicles [69] and may increase lysosomal peptide-MHC stability [70] , and the diversity of T cell epitopes presented [71] . Additionally, a deficiency of C1q can lead to suboptimal antigen uptake, impaired DC differentiation and maturation, and reduced T cell responses [64, [72] [73] [74] [75] [76] [77] . DC present exogenous antigen in a MHC class I-restricted manner, leading to the activation of naïve CD8 + T cells through crosspresentation [78] . DC uptake of complement containing immune complexes (IC) enhances the efficiency of protein antigen crosspresentation compared to free antigens [77, 79, 80] . However, C1q may not be necessary to stimulate T cell priming against pathogenderived antigens [81, 82] .

To minimize recognition and/or destruction by complement several different families of viruses have evolved strategies to evade or exploit complement to establish infection (reviewed in [83] [84] [85] [86] [87] ). Complement evasion mechanisms include: (a) use of complement receptors to enhance viral entry or suppress adaptive immune response (e.g., HIV, West Nile virus (WNV), measles virus, adenoviruses, herpesviruses, enteroviruses, hepatitis B and C viruses ); (b) expression of viral proteins that directly inhibit complement (e.g., herpesviruses, coronaviruses, and astroviruses [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] ); (c) modulation of expression of complement regulators on host cells to prevent complement-dependent lysis (e.g., herpesviruses [137] [138] [139] ); (d) incorporation of human regulators on the surface of virions to protect from complement-mediated virolysis (e.g. HIV, HTLV, cytomegalovirus, and vaccinia virus [140] [141] [142] [143] [144] [145] [146] ); (e) recruitment of soluble complement regulatory proteins to the virion or infected cell surface (e.g., WNV and HIV [147] [148] [149] [150] [151] ); (f) expression of viral decoy proteins that structurally or functionally mimic complement regulatory proteins (e.g., poxviruses and herpesviruses [152] [153] [154] [155] [156] [157] [158] [159] . A single virus may utilize several independent strategies to escape from recognition and targeting by complement and modulate the immune response to establish persistent infection.

Although complement activation inhibits infection of many viruses [160] [161] [162] [163] [164] [165] [166] , it appears to have both protective and pathogenic roles in Flavivirus infection depending on the specific virus, phase of the infection, and immune status of the host. The genus Flavivirus is composed of 73 enveloped viruses containing ∼11 kilobase single-stranded, positive-polarity RNA genomes [167] . Within this family, several are associated with severe human diseases including dengue (DENV), yellow fever (YFV), WNV, Japanese encephalitis (JEV), and tick-borne encephalitis (TBE) viruses [167] . A single open reading frame is translated in the cytoplasm as a polyprotein and cleaved by virus-and host encoded-proteases into three structural (capsid (C), membrane (prM/M), and envelope (E)) and seven nonstructural (NS) proteins including NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 [168] . The E protein functions in receptor binding, entry, and membrane fusion and elicits the majority of neutralizing antibodies whereas prM assists in folding, assembly, and function of the E protein [168] . Viral particles assemble at the endoplasmic reticulum and are released by exocytosis following transport through the trans-Golgi network [168] .

Flavivirus non-structural proteins regulate viral transcription, replication, and attenuation of host antiviral immune response, including antagonizing the interferon response (reviewed in [168] ). One non-structural proteins, NS1, has been recently shown to regulate complement function (see below). NS1 is synthesized as a monomer and dimerizes after post-translational modification [169, 170] . Within the cytoplasm, NS1 acts as a co-factor for the NS5 RNA-dependent RNA polymerase during viral replication [171, 172] . However, it is also expressed on the cell surface and secreted as a hexamer [169, 173] . NS1 has been implicated in the pathogenesis of severe DENV infection [174] [175] [176] and immune evasion by WNV [147, 177] .

Complement can limit Flavivirus infection by stimulating adaptive immune responses. C3 −/− mice are more susceptible to lethal WNV infection and show greater viral burden and reduced antiviral antibody titers [178] . Infection studies with mice lacking C1q, C4, or factor B suggest that all complement activation pathways orchestrate protection against WNV infection [81] . However, each activation pathway appears to exert somewhat distinct protective effects in response to WNV infection. Humoral IgM responses to WNV likely depend upon activation of C3 by the lectin recognition pathway. In contrast, both the lectin and alternative pathways appear necessary for efficient T cell priming as C4 −/− , factor B −/− , and factor D −/− mice exhibited reduced WNV-specific CD8 + T cell responses [81] . The T cell defects in C4 −/− mice may be indirect as depressed IgM responses could affect viral opsonization and antigen presentation.

Flaviviruses also directly trigger complement activation in vitro and in vivo. Increasing concentrations of complement or serum neutralize as much as 60% of a given infectious dose of WNV in cell culture in the absence of antibody [178] . Complement activation by Flaviviruses also has been described in vivo. C3 and C4 consumption were observed in a mouse model of WNV infection prior to the induction of a specific antibody response [81] . C3 catabolism and production of complement split products during secondary DENV infection correlate with increased disease severity and development of dengue hemorrhagic fever and shock syndrome, the most severe form of DENV infection [174, [179] [180] [181] .

Complement activation augments antibody-mediated neutralization of several viruses, including influenza [165, 182] , HIV [183] [184] [185] [186] , respiratory syncytial [187, 188] , varicella zoster [189] [190] [191] , Epstein-Barr [192, 193] , and herpes simplex viruses [194] [195] [196] . Complement also improves antibody-mediated neutralization of Flaviviruses. Complement augments immune serummediated neutralization of YFV, DENV, and Kunjin virus [197] [198] [199] and monoclonal antibody-dependent neutralization of WNV [178] . Similarly, the protective efficacy of Flavivirus neutralizing antibodies in vivo correlates with IgG subclasses that efficiently fix complement [200] .

Fc-␥R engagement by antibodies in vitro can paradoxically enhance replication of Flaviviruses [201] [202] [203] [204] [205] [206] . This phenomenon, known as antibody-dependent enhancement of infection (ADE), is hypothesized to contribute to the pathogenesis of secondary DENV infection [203, 207] . Recent studies indicate that complement can restrict ADE. Complement minimized ADE of WNV and DENV infection in Fc-␥R-expressing cell lines and primary macrophages [208, 209] . Experiments with mouse sera deficient in individual complement components indicate that C1q is sufficient to restrict ADE of WNV infection in vitro. This effect was IgG subclassdependent, as C1q restricted ADE by a human IgG 3 isotype-switch variant, but had little effect on IgG 2 and IgG 4 subclass variants [208] ; these results correlate with the known affinity of human IgG subclasses for C1q [210, 211] . Interestingly, complement-dependent inhibition of DENV ADE may also require C3 [209] . While these studies establish that complement restricts ADE by Flaviviruses, the precise inhibitory mechanisms at the cellular level remain unclear.

Recent studies suggest that C1q also limits Flavivirus ADE in vivo. Whereas enhancement of WNV infection was not observed after passive transfer of antiviral IgG 2a mAbs that bind C1q avidly in wild type mice, it was observed in C1q −/− mice [208] . The ability of C1q to suppress ADE may explain some of the difficulties in consistently observing Flavivirus ADE in animal models. Further investigation is necessary to define the links between complement restriction of ADE, Fc-␥R specificity, and disease pathogenesis of Flaviviruses.

In cells that express CR3, antibody-dependent complement activation may paradoxically enhance viral infection. Complement activation by antiviral IgM enhanced WNV infection of macrophages and monocyte cell lines [92, 93] . Blockade of CR3 abrogated the complement-dependent enhancement of WNV infection in this model system. Thus, under certain circumstances, antibody and complement-dependent opsonization of Flaviviruses may increase infection in CR3-expressing cells.

During severe secondary DENV infection, a vascular leakage syndrome occurs with fluid transudation into serosal spaces [212] . Although the pathogenesis of DENV infection remains controver-sial and implicates cross-reactive antibodies and effector T cells (reviewed in [213] [214] [215] ), a pathological role for complement activation has been suggested. In early clinical studies, reduced levels of C3, C4 and factor B and increased catabolic rates of C3 and C1q were observed, particularly in patients with severe disease [179, 180] . Additionally, C3 breakdown products and anaphylatoxins accumulated in the circulation of severely ill patients and peaked at the day of maximum vascular leakage [181, 216] . Circulating immune complexes formed by virions and DENV-specific antibodies were hypothesized to cause the pathological complement activation [180] , although only small amounts were detected in circulation [181, 217] . One alternative hypothesis is that infected cells express sufficient amounts of DENV antigens (E or NS1 proteins) on their surface facilitating immune complex formation and complement deposition [218] . Indeed, DENV-infected endothelial cells activate human complement in the presence of antibodies resulting in C5b-9 deposition [219] . A subsequent study implicated NS1 as the key surface viral protein responsible for complement activation [174] . As soluble DENV NS1 differentially binds to cultured endothelial and mesothelial cells [175] , high levels of intravascular soluble NS1, as observed in DENV-infected patients, could promote binding and surface expression of NS1 on selective cells without a requirement for direct viral infection; this could contribute to tissue-specific vascular leakage that occurs during severe secondary DENV infection after recognition by anti-NS1 antibodies, immune complex formation, and inflammatory damage [174, 219] .

Recent evidence suggests WNV NS1 has immune evasion function and protects against complement activation by binding the negative regulator factor H [147] . Factor H sustains factor Imediated cleavage of C3b and inactivates the alternative pathway C3 convertase (reviewed in [220] ). Co-immunoprecipitation experiments demonstrate that soluble WNV NS1 binds to factor H, leading to degradation of C3b in solution [147] . Additionally, cell surface NS1 limits C3b deposition and C5b-9 MAC formation [147] . Thus, secreted or cell surface NS1 may minimize immune system targeting of WNV by decreasing complement activation in solution and on the surface of infected cells. This data appears to contradict early studies that suggested DENV NS1 might be the key viral protein that triggers complement activation [221, 222] . In those studies, NS1 was termed "non-hemagglutinating soluble complement fixing antigens (SCF)" because it has activity in the traditional standard complement fixing test that requires specific antibodies to trigger guinea pig complement [221, 222] . Subsequent experiments indicate that DENV NS1 does not activate complement efficiently, but instead requires specific anti-NS1 antibodies for complement consumption and C5b-9 generation ( [174] and Avirutnan et al., unpublished results). Additionally, DENV NS1 has been reported to bind to clusterin, a complement regulator that inhibits MAC formation [223] . Clearly, more studies are necessary to establish the significance of these findings in the pathogenesis of infection of DENV, WNV, and other Flaviviruses in vivo.

Activation of the complement system has a critical role in protection and possibly pathogenesis of infection by different Flaviviruses. Complement activation primes adaptive immune responses and modulates the effector functions of Flavivirus-specific antibodies. Recent studies suggest that Flaviviruses have evolved novel strategies to limit complement activation. The balance between complement activation and evasion likely helps determine the out-come of a productive infection. A greater understanding of how complement restricts and contributes to pathogenesis of individual Flaviviruses may expand strategies for developing therapeutics or vaccines to control infection.

Complement. First of two parts

Second of two parts

Continual low-level activation of the classical complement pathway

Platelet-activating factor and kinin-dependent vascular leakage as a novel functional activity of the soluble terminal complement complex

Intracerebroventricular injection of the terminal complement complex causes inflammatory reaction in the rat brain

Cytolytically inactive terminal complement complex causes transendothelial migration of polymorphonuclear leukocytes in vitro and in vivo

Soluble complex of complement increases hydraulic conductivity in single microvessels of rat lung

Transient perturbation of endothelial integrity induced by natural antibodies and complement

The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity

Regulation of the complement membrane attack pathway

The anaphylatoxins bridge innate and adaptive immune responses in allergic asthma

The complement system in regulation of adaptive immunity

CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens

The regulators of complement activation (RCA) gene cluster

Mapping of the sites responsible for factor I-cofactor activity for cleavage of C3b and C4b on human C4b-binding protein (C4bp) by deletion mutagenesis

Structure-function relationships of complement receptor type 1

Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46)

Functional properties of membrane cofactor protein of complement

Human alternative complement pathway: membrane-associated sialic acid regulates the competition between B and beta1 H for cell-bound C3b

Structure-function analysis of the active sites of complement receptor type 1

Decay accelerating activity of complement receptor type 1 (CD35). Two active sites are required for dissociating C5 convertases

Human C4-binding protein. I. Isolation and characterization

Control of the amplification convertase of complement by the plasma protein beta1H

Membrane defence against complement lysis: the structure and biological properties of CD59

Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers

Incorporation of SP-40,40 into the soluble membrane attack complex (SMAC, SC5b-9) of complement

Molecular structure and functional characterization of a human complement cytolysis inhibitor found in blood and seminal plasma: identity to sulfated glycoprotein 2, a constituent of rat testis fluid

Molecular cloning and characterization of the novel, human complement-associated protein, SP-40,40: a link between the complement and reproductive systems

Potent inhibition of terminal complement assembly by clusterin: characterization of its impact on C9 polymerization

Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9

Complement S-protein (vitronectin) is associated with cytolytic membrane-bound C5b-9 complexes

Vitronectinmediated inhibition of complement: evidence for different binding sites for C5b-7 and C9

Structural and functional aspects of C1-inhibitor

The role of complement and complement receptors in induction and regulation of immunity

Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex

Identification of a 145,000 Mr membrane protein as the C3d receptor (CR2) of human B lymphocytes

Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19

C3d of complement as a molecular adjuvant: bridging innate and acquired immunity

Enhancement of antibodies to the human immunodeficiency virus type 1 envelope by using the molecular adjuvant C3d

C3d enhancement of antibodies to hemagglutinin accelerates protection against influenza virus challenge

Fusion to C3d enhances the immunogenicity of the E2 glycoprotein of type 2 bovine viral diarrhea virus

Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen

Antibody response to a T-dependent antigen requires B cell expression of complement receptors

Regulation of the B cell response to T-dependent antigens by classical pathway complement

Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2

B lymphocyte memory: role of stromal cell complement and FcgammaRIIB receptors

Dependence of germinal center B cells on expression of CD21/CD35 for survival

Impaired affinity maturation in Cr2−/− mice is rescued by adjuvants without improvement in germinal center development

Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte

Complement receptor 1/CD35 is a receptor for mannan-binding lectin

Complement receptor type 1 (CR1 CD35) is a receptor for C1q

Expression of C3b receptors on human be cells and myelomonocytic cells but not natural killer cells

Both Kupffer cells and liver endothelial cells play an important role in the clearance of IgA and IgG immune complexes

Clearance of antidouble-stranded DNA antibodies: the natural immune complex clearance mechanism

Their use in a distribution study showing that mouse erythrocytes and platelets are CR1-negative

The murine complement receptor gene family. IV. Alternative splicing of Cr2 gene transcripts predicts two distinct gene products that share homologous domains with both human CR2 and CR1

A molecular and immunochemical characterization of mouse CR2. Evidence for a single gene model of mouse complement receptors 1 and 2

Humoral immune responses in Cr2−/− mice: enhanced affinity maturation but impaired antibody persistence

Complement component C3 promotes T-cell priming and lung migration to control acute influenza virus infection

Complement component 3 is required for optimal expansion of CD8 T cells during a systemic viral infection

Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response

Evidence for an important interaction between a complement-derived CD21 ligand on follicular dendritic cells and CD21 on B cells in the initiation of IgG responses

Local synthesis of complement component C3 regulates acute renal transplant rejection

Natural antibodies and complement are endogenous adjuvants for vaccine-induced CD8+ T-cell responses

C3b covalently associated to tetanus toxin modulates TT processing and presentation by U937 cells

Covalent binding of C3b to tetanus toxin: influence on uptake/internalization of antigen by antigen-specific and non-specific B cells

Antigen-bound C3b and C4b enhance antigenpresenting cell function in activation of human T-cell clones

Modulation of antigen processing and presentation by covalently linked complement C3b fragment

B cell receptors and complement receptors target the antigen to distinct intracellular compartments

Complement C3b fragment covalently linked to tetanus toxin increases lysosomal sodium dodecyl sulfate-stable HLA-DR dimer production

C3b complexation diversifies naturally processed T cell epitopes

Maturation of dendritic cells abrogates C1q production in vivo and in vitro

Complement protein C1q induces maturation of human dendritic cells

Immune modulation of human dendritic cells by complement

T cell-dependent immune response in C1q-deficient mice: defective interferon gamma production by antigen-specific T cells

Immune complex processing in C1q-deficient mice

A novel role of complement factor C1q in augmenting the presentation of antigen captured in immune complexes to CD8+ T lymphocytes

Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens

Antigen-antibody immune complexes empower dendritic cells to efficiently prime specific CD8+ CTL responses in vivo

Immune complex-loaded dendritic cells are superior to soluble immune complexes as antitumor vaccine

Protective immune responses against West Nile virus are primed by distinct complement activation pathways

Complement contributes to protective immunity against reinfection by Plasmodium chabaudi chabaudi parasites

HIV and human complement: inefficient virolysis and effective adherence

Viral mimicry of the complement system

Role of complement in immune regulation and its exploitation by virus

Virus complement evasion strategies

Complement evasion by human pathogens

Cutting edge: productive HIV-1 infection of dendritic cells via complement receptor type 3 (CR3, CD11b/CD18)

Complement dependent trapping of infectious HIV in human lymphoid tissues

Decay-accelerating factor (CD55), a glycosylphosphatidylinositol-anchored complement regulatory protein, is a receptor for several echoviruses

Opsonization of HIV-1 by semen complement enhances infection of human epithelial cells

Interaction of West Nile virus with primary murine macrophages: role of cell activation and receptors for antibody and complement

Complement receptor mediates enhanced flavivirus replication in macrophages

Immune tolerance split between hepatitis B virus precore and core proteins

A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen

Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions

CR1(CD35) and CR2(CD21) complement C3 receptors are expressed on normal human thymocytes and mediate infection of thymocytes with opsonized human immunodeficiency virus

B cellmediated infection of stimulated and unstimulated autologous T lymphocytes with HIV-1: role of complement

Mechanism(s) promoting HIV-1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co-cultures

The human CD46 molecule is a receptor for measles virus (Edmonston strain)

Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation

Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2

CD46 is a cellular receptor for group B adenoviruses

B lymphocytes in lymph nodes and peripheral blood are important for binding immune complexes containing HIV-1

Detachment of human immunodeficiency virus type 1 from germinal centers by blocking complement receptor type 2

C5a and C5a(desArg) enhance the susceptibility of monocyte-derived macrophages to HIV infection

Mechanism of suppression of cell-mediated immunity by measles virus

Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation

Functional modulation of human macrophages through CD46 (measles virus receptor): production of IL-12 p40 and nitric oxide in association with recruitment of protein-tyrosine phosphatase SHP-1 to CD46

In vitro and in vivo interactions between the hepatitis B virus protein P22 and the cellular protein gC1qR

Hepatitis C virus core protein inhibits interleukin 12 and nitric oxide production from activated macrophages

Inhibition of interferon-mediated antiviral activity by murine gammaherpesvirus 68 latency-associated M2 protein

CD46 is a cellular receptor for all species B adenoviruses except types 3 and 7

Binding of human immunodeficiency virus type 1 to the C3b/C4b receptor CR1 (CD35) and red blood cells in the presence of envelope-specific antibodies and complement. National Institutes of Health AIDS Vaccine Clinical Trials Networks

Ligation of CR1 (C3b receptor, CD35) on CD4+ T lymphocytes enhances viral replication in HIV-infected cells

Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d

Complement-mediated enhancement of HIV-1 infection in peripheral blood mononuclear cells

Identification of a cellular protein specifically interacting with the precursor of the hepatitis B e antigen

CD46 is a cellular receptor for human herpesvirus 6

Adenovirus type 11 uses CD46 as a cellular receptor

Selective suppression of IL-12 production by human herpesvirus 6

In vitro analysis of complement-dependent HIV-1 cell infection using a model system

Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis

CR1 (CD35) and CR3 (CD11b/CD18) mediate infection of human monocytes and monocytic cell lines with complementopsonized HIV independently of CD4

Triggering of complement receptors CR1 (CD35) and CR3 (CD11b/CD18) induces nuclear translocation of NF-kappa B (p50/p65) in human monocytes and enhances viral replication in HIV-infected monocytic cells

HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production

Human astrovirus coat protein inhibits serum complement activation via C1, the first component of the classical pathway

Antibody-induced and cytoskeleton-mediated redistribution and shedding of viral glycoproteins, expressed on pseudorabies virus-infected cells

Identification of a novel herpes simplex virus type 1-induced glycoprotein which complexes with gE and binds immunoglobulin

Herpes simplex virus immunoglobulin G Fc receptor activity depends on a complex of two viral glycoproteins, gE and gI

Mechanism of complement inactivation by glycoprotein C of herpes simplex virus

Herpesviral Fc receptors and their relationship to the human Fc receptors

Herpes simplex virus type 1 evades the effects of antibody and complement in vivo

In vivo immune evasion mediated by the herpes simplex virus type 1 immunoglobulin G Fc receptor

Molecular mimicry between S peplomer proteins of coronaviruses (MHV, BCV, TGEV and IBV) and Fc receptor

Identification and expression of a murine cytomegalovirus early gene coding for an Fc receptor

Mechanism of host cell protection from complement in murine cytomegalovirus (CMV) infection: identification of a CMV-responsive element in the CD46 promoter region

Altered expression of hostencoded complement regulators on human cytomegalovirus-infected cells

Human herpesvirus 7 infection increases the expression levels of CD46 and CD59 in target cells

Acquisition of host cell-surface-derived molecules by HIV-1

Decay-accelerating factor (CD55) protects human immunodeficiency virus type 1 from inactivation by human complement

Antibodydependent complement-mediated cytotoxicity in sera from patients with HIV-1 infection is controlled by CD55 and CD59

Mechanisms of resistance of HIV-1 primary isolates to complement-mediated lysis

Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope

Human immunodeficiency virus type 1 incorporates both glycosyl phosphatidylinositol-anchored CD55 and CD59 and integral membrane CD46 at levels that protect from complement-mediated destruction

Host cell-derived complement control proteins CD55 and CD59 are incorporated into the virions of two unrelated enveloped viruses. Human T cell leukemia/lymphoma virus type I (HTLV-I) and human cytomegalovirus (HCMV)

West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H

Direct interaction of complement factor H with the C1 domain of HIV type 1 glycoprotein 120

HIV glycoprotein 41 and complement factor H interact with each other and share functional as well as antigenic homology

Human complement proteins C3b, C4b, factor H and properdin react with specific sites in gp120 and gp41, the envelope proteins of HIV-1

Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55)

Herpesvirus saimiri has a gene specifying a homologue of the cellular membrane glycoprotein CD59

The complement control protein homolog of herpesvirus saimiri regulates serum complement by inhibiting C3 convertase activity

Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation

Regulation of complement activity by vaccinia virus complement-control protein

The cowpox virus-encoded homolog of the vaccinia virus complement control protein is an inflammation modulatory protein

Variola virus immune evasion design: expression of a highly efficient inhibitor of human complement

Functional characterization of the complement control protein homolog of herpesvirus saimiri: ARG-118 is critical for factor I cofactor activities

Complement regulation by Kaposi's sarcoma-associated herpesvirus ORF4 protein

The relevance of complement to virus biology

The effect of complement depletion on the course of Sindbis virus infection in mice

Role of complement in viral infections: participation of terminal complement components (C5 to C9) in recovery of mice from Sindbis virus infection

The role of complement in viral infections. II. The clearance of Sindbis virus from the bloodstream and central nervous system of mice depleted of complement

Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity

Enhancement of neutralizing activity of influenza virus-specific antibodies by serum components

The role of the complement system in virus infections

Fields' virology

Flaviviridae: the viruses and their replication

Newly synthesized dengue-2 virus nonstructural protein NS1 is a soluble protein but becomes partially hydrophobic and membrane-associated after dimerization

Evidence that the mature form of the flavivirus nonstructural protein NS1 is a dimer

Genetic interaction of flavivirus nonstructural proteins NS1 and NS4A as a determinant of replicase function

Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication

Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion

Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement

Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E

High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever

West Nile virus nonstructural protein 1 inhibits TLR3 signal transduction

Complement activation is required for induction of a protective antibody response against West Nile virus infection

Pathogenetic mechanisms in dengue haemorrhagic fever: report of an international collaborative study

The potential pathogenic role of complement in dengue hemorrhagic shock syndrome

Complement and dengue haemorrhagic fever/shock syndrome

Neutralization of influenza virus by normal human sera: mechanisms involving antibody and complement

Detection of antibody-dependent complement-mediated inactivation of both autologous and heterologous virus in primary human immunodeficiency virus type 1 infection

Functional activity of an HIV-1 neutralizing IgG human monoclonal antibody: ADCC and complement-mediated lysis

Complement activation by human monoclonal antibodies to human immunodeficiency virus

Broad neutralization and complement-mediated lysis of HIV-1 by PEHRG214, a novel caprine anti-HIV-1 polyclonal antibody

Effect of complement and viral filtration on the neutralization of respiratory syncytial virus

Role of complement in neutralization of respiratory syncytial virus

Neutralization of vesicular stomatitis virus (VSV) by human complement requires a natural IgM antibody present in human serum

Complement-enhanced neutralizing antibody response to varicella-zoster virus

Neutralizing antibody responses to varicella-zoster virus

Neutralization of Epstein-Barr virus by nonimmune human serum. Role of cross-reacting antibody to herpes simplex virus and complement

Complement-dependent, Epstein-Barr virus-neutralizing antibody appearing early in the sera of patients with infectious mononucleosis

Serologic responses to herpes simplex virus in rabbits: complement-requiring neutralizing, conventional neutralizing, and passive hemagglutinating antibodies

Complement requirement for virus neutralization by antibody and reduced serum complement levels associated with experimental equine herpesvirus 1 infection

Herpesvirus neutralization: the role of complement

Immune response in rabbits to virion and nonvirion antigens of the Flavivirus kunjin

The dengue group of viruses and its family relationships

Yellow fever virus. II. Factors affecting the plaque neutralization test

Neutralizing F(ab )2 fragments of protective monoclonal antibodies to yellow fever virus (YF) envelope protein fail to protect mice against lethal YF encephalitis

Flavivirus infection enhancement in macrophages: radioactive and biological studies on the effect of antibody on viral fate

Flavivirus infection enhancement in macrophages: an electron microscopic study of viral cellular entry

Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody

Antibody-dependent enhancement of dengue virus growth in human monocytes as a risk factor for dengue hemorrhagic fever

Monoclonal anti-Fc receptor IgG blocks antibody enhancement of viral replication in macrophages

Antibody-mediated enhancement of Flavivirus replication in macrophage-like cell lines

Pathogenesis of dengue: challenges to molecular biology

Complement protein C1q inhibits antibody-dependent enhancement of flavivirus infection in an IgG subclass-specific manner

Infection-enhancing and -neutralizing activities of mouse monoclonal antibodies against dengue type 2 and 4 viruses are controlled by complement levels

Human monoclonal IgG isotypes differ in complement activating function at the level of C4 as well as C1q

The classical complement pathway: activation and regulation of the first complement component

Clinical spectrum and management of dengue haemorrhagic fever

Immunopathological mechanisms in dengue and dengue hemorrhagic fever

Dengue hemorrhagic fever with special emphasis on immunopathogenesis

Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS)

Crossed immunoelectrophoresis for the detection of split products of the third complement in dengue hemorrhagic fever. I. Observations in patients' plasma

The Raji cell radioimmune assay for detecting immune complexes in human sera

Pathogenesis of dengue: an alternative hypothesis

Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis

Factor H family proteins: on complement, microbes and human diseases

Partial purification and characterization of a dengue virus soluble complement-fixing antigen

Molecular size and charge relationships of the soluble complement-fixing antigens of dengue viruses

Secreted complement regulatory protein clusterin interacts with dengue virus nonstructural protein 1