key: cord-0690130-8tuer1yv
authors: Iyer, Kruthika; Chand, Kailash; Mitra, Alapani; Trivedi, Jay; Mitra, Debashis
title: Diversity in heat shock protein families: functional implications in virus infection with a comprehensive insight of their role in the HIV-1 life cycle
date: 2021-07-27
journal: Cell Stress Chaperones
DOI: 10.1007/s12192-021-01223-3
sha: f5413a75cab51e47915faaba3adfa86d10b6f4b7
doc_id: 690130
cord_uid: 8tuer1yv

Heat shock proteins (HSPs) are a group of cellular proteins that are induced during stress conditions such as heat stress, cold shock, UV irradiation and even pathogenic insult. They are classified into families based on molecular size like HSP27, 40, 70 and 90 etc, and many of them act as cellular chaperones that regulate protein folding and determine the fate of mis-folded or unfolded proteins. Studies have also shown multiple other functions of these proteins such as in cell signalling, transcription and immune response. Deregulation of these proteins leads to devastating consequences, such as cancer, Alzheimer’s disease and other life threatening diseases suggesting their potential importance in life processes. HSPs exist in multiple isoforms, and their biochemical and functional characterization still remains a subject of active investigation. In case of viral infections, several HSP isoforms have been documented to play important roles with few showing pro-viral activity whereas others seem to have an anti-viral role. Earlier studies have demonstrated that HSP40 plays a pro-viral role whereas HSP70 inhibits HIV-1 replication; however, clear isoform-specific functional roles remain to be established. A detailed functional characterization of all the HSP isoforms will uncover their role in cellular homeostasis and also may highlight some of them as potential targets for therapeutic strategies against various viral infections. In this review, we have tried to comprehend the details about cellular HSPs and their isoforms, their role in cellular physiology and their isoform-specific functions in case of virus infection with a specific focus on HIV-1 biology.

Heat shock proteins (HSPs) are one of the most evolutionarily conserved groups of cellular proteins found across almost all the living organisms. In humans, these proteins are known to be modulated upon stress conditions such as heat stress, cold shock, ultraviolet (UV) irradiation, exposure to heavy metals and microbial infection. The stress signal is usually a flux of non-native proteins that triggers the activation of heat shock factors (HSF), which in turn results in the change in expression of HSPs (Pirkkala et al. 2001) (Fig. 1) . HSPs, also referred to as molecular chaperones, have been well characterized for their roles in housekeeping functions such as protein folding, assembly, transport and degradation (Georgopoulos and Welch 1993; Parsell et al. 1993; Becker and Craig 1994) . However, studies have later shown multiple other functions of these proteins such as in cell signalling pathways, transcription regulation and immune response. Mammalian HSPs have been initially classified into different groups based on their molecular weight such as small heat shock proteins, HSP40, HSP70, HSP90, HSP100 and chaperonins (Csermely et al. 1998 ). However, in 2009, they were renamed as HSPB, DNAJ, HSPA, HSPC, HSPH and chaperonin/CCT/HPD, respectively (Kampinga et al. 2009 ). Interestingly, each family of cellular HSPs are now known to comprise several members or isoforms as listed in Table 1 . The number varies vastly from one family to the other as highlighted in the table. The main function of many of these isoforms is yet to be characterized, although they seem to be highly conserved across different species and various homologues are found in even some of the most primitive organisms such as archaea, bacteria and fungi (Feder and Hofmann 1999; Large et al. 2009 ). Heat shock proteins were first discovered in the fruit fly Drosophila melanogaster chromosomal puffs, when they were placed in temperatures above 36°C (Ritossa 1962) . Since then, heat shock proteins have been extensively investigated for their role in several biological process such as apoptosis (Takayama et al. 2003) , neuro-degeneration and aging (Leak 2014) , development (Miller and Fort 2018) and immunomodulation (Zininga et al. 2018) , in addition to their chaperone function.

Intensive exploration of HSPs and their role in the past few decades have highlighted them as potential therapeutic targets not only for various diseases including cancer and autoimmune conditions but also for viral infections. For example, the adenoviral E1A gene induces the 70-kDa heat-inducible HSP70 gene expression in HeLa cells (Nevins 1982) . Many reports have shown HSP modulation during herpes simplex virus (HSV) infection. A latent infection of HSV type 2 causes an increase in the 90-kDa, 70-kDa and 72-kDa cellular heat stress proteins in human neuroblastoma cells (Yura et al. 1987) . Both HSV-1 and HSV-2 infection in mouse L cells causes an increase in the HSP70 mRNA levels within 4 h post infection (Kobayashi et al. 1994) . EBV (Epstein-Barr virus) infection of human B lymphocytes induces HSP70 and HSP90 at the mRNA and protein levels which is dependent on the EBV-induced trans-membrane Ca 2+ currents (Cheung and Dosch 1993) . Modulation of HSPs has been observed during RNA virus infections as well. HSP70 associates with the capsid precursor P1 of poliovirus type 1 and coxsackievirus B1 (Macejak and Sarnow 1992) . Studies have shown that HSP70 was expressed on the cell surface of the HTLV-1-transformed cells. Human immunodeficiency virus (HIV), another well-known retrovirus, causes an increase in HSP70 in chronically infected lymphoma cells (Di Cesare et al. 1992 ) and lymphocytes from HIV-infected patients (Agnew et al. 2003) . There is also an increase in the levels of HSP40 (Kumar and Mitra 2005; Solis et al. 2006) .

Although a number of reviews are available regarding the role of HSPs in various physiological processes and disease conditions including pathogenic insults with viral infections, due to lack of availability in literature related to the function of Heat shock protein B (HSPB/sHSP family)

Small HSP (sHSP) are a group of ten (HSPB1-10) proteins having a molecular weight from 15 to 30 kDa, which are normally present as large oligomers at basal levels. They were first discovered in the chromosomal puffs of Drosophila melanogaster upon heat shock and ecdysterone treatment (Tissiéres et al. 1974) . The members of this family have a conserved C-terminal domain, homologous to alpha crystallin of the vertebrate eye lens (Kim et al. 1998 ). The length of the C-terminus is highly flexible and has a conserved sequence, a IXI/V motif. The N-terminus domain, also called the WDPF domain (as it contains this amino acid sequence), is highly variable (Lelj-Garolla and Mauk 2006) (Fig. 2a ). There are two alpha crystallin genes, alpha A and alpha B. These proteins are a major component of the vertebrate eye lens. In the early 1990s, it was discovered that alpha B crystallin is a small heat shock protein (Klemenz et al. 1991) . Alpha A crystallin confers thermo-resistance to cells upon overexpression (van den Ijssel et al. 1994 ) and also acts as a molecular chaperone outside of its role as a major lens protein (Horwitz 1992) . HSP27 is one of the most studied members of the sHSP family. The protein is phosphorylated by p38 MAPK in vivo at multiple serine residues (Gaestel et al. 1991; Landry et al. 1992; Guay et al. 1997) . It then forms smaller oligomers (Mehlen et al. 1997; Rogalla et al. 1999) , and the phosphorylated form regulates many of its functions. HSP27 has been documented to respond to different types of cellular stress. During oxidative stress, it acts as an antioxidant by lowering reactive oxygen species by decreasing iron levels (Mehlen et al. 1997; Arrigo 2001; Arrigo et al. 2005) . During chemical stress, HSP27 acts as an anti-apoptotic agent. It binds DAXX during Fas-FasL-mediated apoptosis (Charette and Landry 2000) and prevents mitochondria-dependent apoptosis by interacting with cytochrome c and indirectly inhibiting Bax (Bruey et al. 2000; Havasi et al. 2008) . It has been observed that the levels of HSP27 significantly increase in many disease states such as renal injury, renal fibrosis, cancer, cardiovascular disease, neurodegenerative disease, and neuronal injury (Vidyasagar et al. 2012) .

HSP27 has been implicated in viral infections also. In human adenovirus-infected cells, HSP27, p38 MAPK and NFκB-p65 form a signalling complex that affects downstream pro-inflammatory mediators (Rajaiya et al. 2012) . HSP27 cellular localization is modified and reorganized during HSV-1 infection, and furthermore, replication of the virus is drastically reduced upon depletion of the HSP27 (Mathew et al. 2009 ).

The same is the case in Enterovirus (EV-A71) infection where HSP27 was increased upon infection whereas knockout of HSP27 results in reduced viral replication (Dan et al. 2019 ).

The converse of what happens in other viruses occurs in swine fever virus wherein depletion of HSP27 increases virus replication. Ectopic expression reduces replication through activation of NF-κB signalling in PK-15 cells. HSP27 was also shown to interact with NS5A, a non-structural protein, as a response to viral replication and assembly (Ling et al. 2018) . In hepatitis B virus, HSP27 levels are increased in infected human liver tissues and virus-producing HepG2.2.15 cells (Tong et al. 2013) . The studies on HSP27 in different viruses indicate its role as both a pro-viral and antiviral factor through various mechanisms involving different signalling pathways. On the other hand, work done on the role of sHSPs or even HSP27 in HIV-1 infection is quite limited. In an early study, it was shown that in HIV-1 chronically infected monocytic and lymphocytic CD4 + T-cell lines, there is a 2-to 15-fold increase in HSP27 production (Brenner et al. 1995) . They also showed that there is an early increase in HSP27 mRNA and protein, which is short-lived and declines during initiation of de novo viral synthesis. The levels again rise in the late stages of infection when there is maximal viral production and CD4 cytolysis (Wainberg et al. 1997) . In 2007, Liang et al. investigated cellular proteins that can suppress the viral protein R (Vpr) function of HIV-1. Increased levels of HSP27 inhibit Vpr-induced cell cycle G2 arrest (Liang et al. 2007) , and activation of HSP27 by Vpr is mediated through HSF1. HSP27 seems to suppress Vpr activities, and Vpr in turn inhibits a prolonged expression of HSP27 in heat shocked cells. The role of HSP27 in other virus infections through NF-κB has been highlighted earlier, and NF-κB is also central to the functions of HIV-1 Vpr during the virus life cycle (Varin et al. 2005; Kogan et al. 2013 ). However, the link between HSP27, NF-κB and Vpr, if any, has not yet been well explored and may be worth looking into. CD8+ CD57+ lymphocytes, a population that expands during HIV infection and other chronic conditions, show a constitutive expression of HSP27 (Wood et al. 2010) . Low HSP27 levels coincided with increased apoptosis of the cells and vice versa. Apart from showing the early induction of HSP27 during HIV-1 infection, Brenner and Wainberg also indicated the role of HSP27 and HSP70 as vaccine adjuvants due to their ability to interact with viral proteins and also redistribute themselves to the surface of the plasma membrane (Brenner and Wainberg 1999) . In 2017, Milani et al. further added to this body of work, by illustrating the use of HSP27-Nef fusion DNA or protein to elicit high humoral and cellular immune responses (Milani et al. 2017 (Milani et al. , 2020 . Further exploration in this area could help the HIV-AIDS community in developing a vaccine.

The literature on the role of alpha crystallins (HSPB4 and HSPB5) on HIV pathogenesis is very limited. One study reported that alpha crystallins bound to calcium ions assist in the folding of HIV-1 protease through a molten-globule-like intermediate (Dash et al. 2005) . Another isoform of the sHSP family, HSPB8 regulates Sam68, a protein that enhances Rev response element-mediated gene expression and viral production. HSPB8 actually inhibits the function of Sam68 in this pathway through its binding with Sam68 (Badri et al. 2006) . Further studies in elucidating the role of these sHSP isoforms in virus infection could be very useful.

The HSP40/DNAJ (heat shock protein 40) family is defined as a group of proteins that are orthologs of the E. coli HSP40 (DNAJ) protein. The DNAJ/HSP40 family belongs to a diverse group of co-chaperones which assists HSP70 for proper protein folding, protein transport and degradation. DNAJ/ HSP40 physically interacts with HSP70 through its conserved J domain and increases the ATPase activity of HSP70 (Cheetham and Caplan 1998) . DNAJ/HSP40 is reported to be located in many subcellular compartments such as mitochondria, endoplasmic reticulum, cytosol, nuclei, endosome and ribosomes and extracellular environment of eukaryotes and cytosol of prokaryotes (Fan et al. 2003; Walsh et al. 2004; Qiu et al. 2006; Kampinga and Craig 2010) . DNAJ/ HSP40 plays a vital role in the expression of genes, initiation of translation, translocation, degradation and folding/ unfolding of proteins. It binds to unfolded or non-native polypeptides and prevents their aggregation (Fan et al. 2003) . DNAJ/HSP40 is also linked with folded proteins, which results in the "remodelling" of large multi-protein complexes and hence thought to be regulating the balance of protein/ protein interactions (Kampinga and Craig 2010) .

The human genome encodes about 49 isoforms of DNAJ/ HSP40 protein, which show significant diversity at the primary sequence level. These isoforms show variability in the size which ranges from~10 kDa (DNAJC19) to~504 kDa (DNAJC29). The DNAJ/HSP40 protein consists of four typical domains, an N-terminal highly conserved sequence of about 70 amino acids known as signature J-domain, followed by a Gly/Phe-rich region (G/F-rich domain), zinc finger domain (four repeats of the CxxCxGxG type) and a less conserved C-terminal substrate-binding domain. The members of the DNAJ/HSP40 family have been categorized majorly into three groups: type I (group A) proteins comprise all four domains; in type II (group B) proteins, the zinc-finger domain is absent; and type III (group C) proteins retain only the signature J-domain, located at any position in the protein sequence ( Fig. 2b) .

The DNAJ/HSP40 family has been implicated in various human diseases like neurodegenerative disorders (Muchowski et al. 2000; Sherman and Goldberg 2001) , autoimmune diseases (Albani et al. 1995; Chukwuocha et al. 1999; Tukaj et al. 2010) , cancer (Mitra et al. 2009 ) and microbial infections (Neckers and Tatu 2008) . DNAJ/HSP40 family members are found to be modulated during various neuro-degenerative diseases like DNAJB6 in Huntington's disease (Orr and Zoghbi 2007; Wetzel 2012; Månsson et al. 2014 ) and DNAJC13 in Parkinson's disease (Rajput et al. 2015) . Various reports also show that few members of the DNAJ family are associated in different types of cancers such as DNAJC15 in human ovarian tumours (Shridhar et al. 2001) , DNAJA3 in gliomas (Trentin et al. 2004 ) and colon cancer (Kurzik-Dumke et al. 2008), DNAJB4 in lung cancer (Tsai et al. 2006 ) and DNAJC12 in breast tumours (De Bessa et al. 2006) .

In case of viral infections, the HSP40/DNAJ family has been identified to regulate the replication of various viruses. Although the HSP40 family comprises several members, it has been earlier considered and represented as one protein in several studies. In one such report, it was shown that HSP40 interacts with matrix protein (M2) and p58 IPK protein of influenza virus (A/B) and regulates PKR signalling pathway in influenza-infected cells (Melville et al. 1997; Guan et al. 2010) . In case of hepatitis B virus infection, HSP40 helps in the priming and activation of reverse transcriptase enzyme and enhances the viral replication Nassal 2003, 2007) . HSP40 has also been reported to interact with the 3′ end of RNA of murine hepatitis virus to possibly promote its stability (Nanda et al. 2004) . Similarly, HSP40 interaction with the nucleotide-binding domain (NBD) of HSP70 is crucial for its stronger binding with viral nucleocapsid protein, which stimulates the transcription and genome replication of measles virus (Couturier et al. 2010) . HSP40 was also shown to interact with E1 helicase of human papillomavirus and enhance its binding to the origin of DNA replication (Liu et al. 1998; Lin et al. 2002) . Similarly, in case of herpes simplex virus-1 infection, HSP40 enhances the binding of viral initiator protein (UL9) with origin of the DNA replication site and stimulates viral replication (Le Gac and Boehmer 2002) .

As is the case with other heat shock protein families, studies on the isoform-specific role of the HSP40 family has emerged only since the early 2000s. Some of the DNAJ/ HSP40 family isoforms have been reported to regulate the pathogenesis of several viruses. It has been reported that DNAJA1 associates with the bPB2 and PA subunits of RNA-dependent RNA polymerase (RdRp) of the influenza A virus through its C-terminal substrate-binding region and translocate into the nucleus to enhance viral RNA synthesis independent of HSP70 (Cao et al. 2014) . DNAJA1 is also reported to regulate the replication of Japanese encephalitis virus through interacting with nonstructural protein 5 (NS5). Overexpression of DNAJA1 increases viral RNA synthesis in infected cells (Wang et al. 2011 ). DNAJA3 regulates human T-cell leukaemia virus type 1 (HTLV-1) replication through interaction with Tax, an oncogenic viral protein encoded by HTLV-1 that induces cellular transformation of T-lymphocytes (Cheng et al. 2002) . In case of adenovirus infection, DNAJB1 is activated by Gam-1, a viral encoded protein that regulates viral replication by activating heat shock response (Glotzer et al. 2000) . There is another report which shows that DNAJB6 and DNAJA1 inhibit hepatitis B virus replication and capsid assembly through accelerated degradation of the viral core and HBx proteins (Sohn et al. 2006) . In HBV, DNAJB6 enhances the reverse transcription through binding with Hsc70 independent of HSP90 and other co-factors Nassal 2003, 2007) . DNAJB11, DNAJB12, DNAJB14 and DNAJC18 seem to regulate simian virus (SV40) replication. This virus utilizes ER-localized proteins to initiate disassembly and transit through the cell (Goodwin et al. 2011) . DNAJC14 is recruited to the replication complexes of yellow fever virus and inhibits viral RNA replication (Yi et al. 2011) . Later on, researchers have also shown that HSP40 plays an important role in different steps of the dengue virus life cycle by assisting HSP70 function. They highlighted nine distinct isoforms of HSP40 which are involved at different stages of the virus life cycle; of these, DNAJB11 promotes viral RNA synthesis, while DNAJB6 associates with viral capsid protein and facilitates virion biogenesis (Taguwa et al. 2015) .

In case of HIV-1 infection, there are only few reports which show the importance of the HSP40 family or its members in virus replication or infection progression. Our lab has earlier shown that HIV-1 Nef protein interacts with HSP40 and increases its translocation into the nucleus of infected cells. The isoform involved seems to be DNAJB1. This interaction with Nef enhances the long terminal repeat-mediated viral gene expression by becoming part of the cyclin-dependent kinase 9-associated transcription complex (Kumar and Mitra 2005) .

Apart from this, HSP40 also interacts with HSP70 and they regulate HIV-1 replication in a reciprocal manner where HSP70 acts as an antiviral factor and HSP40 acts as a proviral factor ). There are a few recent studies in which people have shown the isoform-specific role of HSP40 in HIV-1 infection. DNAJ/HSP40 family members such as DNAJB1, DNAJB6, DNAJA1 and DNAJC5 were shown to negatively regulate the HIV-1 replication by downregulating Rev viral protein expression in one study (Urano et al. 2013 ). The DNAJB6-large variant (MRJ-L) interacts with HIV-1 Vpr and regulates HIV-1 replication. An increase in DNAJB6 levels efficiently increases the HIV-1 replication or reduction in DNAJB6 expression decreases HIV-1 production significantly (Chiang et al. 2014; Ko et al. 2019) . In case of HIV-2 infection, DNAJB6 protein interacts with Vpx protein of virus and helps in the nuclear import of the pre-integration complex (PIC). DNAJB6 competes with the Gag precursor protein for the binding of Vpx and enhances the nuclear import of PIC (Cheng et al. 2008) . Recently, our laboratory has shown that during heat stress, only DNAJA4, DNAJB1 and DNAJB4 were upregulated, while during HIV-1 infection, several HSP40 isoforms showed significant upregulation in mRNA expression levels (Chand et al. 2021 ). Modulation of so many isoforms piqued interest in whether all the modulated isoforms are involved in regulating virus replication and infection progression differently or it is just because of the stress induced by virus infection.

Due to the vast number of isoforms present in the HSP40 family, any work done regarding the same only seems to reflect a fraction of the potential of HSP40 isoforms in viral infections. However, our recent study on the expression modulation of these different isoforms during HIV-1 infection makes it all the more necessary to do their further functional characterization.

The family is specifically termed "chaperonin" that represents a particular class of chaperones with a large multimeric double-ring-like cylindrical structure. This structure allows the sequestration of newly synthesized and denatured proteins inside the central cavity for their folding with the help of ATP hydrolysis. The chaperonins are divided into two distantly related subfamilies-group I and group II. The general domain arrangement consists of an N-terminal apical domain needed for peptide binding and recognition. The C-terminal equatorial domain helps in the binding of each subunit and has most of the ATP contact sites. The intermediate domain links the two domains. This regulates the conformational change of the chaperonin (Dun et al. 2012) (Fig. 2c) . The group I members are present in Eubacteria (GroEL), and in eukaryotic organelles of eubacterial descent i.e. mitochondria (HSP60/ HSPD/Cpn60) and chloroplasts (in plants) (Hemmingsen et al. 1988; Mayer 2010; Saibil 2013) . The most well-studied member of the group I chaperonin is Escherichia coli GroEL (~57 kDa) with a double heptameric ring structure (Hohn et al. 1979; Hendrix 1979; Braig et al. 1994) . Following ATP binding, GroEL recruits its single-ring co-chaperonin GroES (~10 kDa) of the same symmetry to f o r m f u n c t i o n a l b a c t e r i a l c h a p e r o n i n c o m p l e x GroEL-GroES. The co-chaperonin caps the central cavity of the complex, inducing structural rearrangements for transition from the open ring to a closed container for protein folding (Chen et al. 1994; Xu et al. 1997) . Unlike the bacterial homolog, the structure and function of the mammalian chaperonin system HSP60-HSP10 have remained unclear. Following mitochondrial import, the mature form of HSP60 (~58 kDa) is primarily involved in mitochondrial protein folding (Cheng et al. 1989; Ostermann et al. 1989 ) and mitochondrial quality control (Magnoni et al. 2014) . Extramitochondrial localizations of HSP60 have also been reported in some studies. The chaperonin has also been found on the surface of both normal (Soltys and Gupta 1997) and tumour cells (Piselli et al. 2000; Feng et al. 2002) . Expression of surface HSP60 on stressed or damaged cells acts as a danger signal that further elicits pro-inflammatory response through the innate immune system (Ohashi et al. 2000) . Similarly, apoptotic tumour cells exhibit an elevated surface expression of HSP60 as an immune biomarker resulting in stimulation of dendritic cells and generation of potent antitumor-specific T-cell responses (Feng et al. 2002) . In addition to its intracellular and surface localizations, HSP60 has also been reported in extracellular space and in circulation. The extracellular HSP60 is associated with both pro-and anti-inflammatory effects through its engagement with several cell surface receptors such as Toll-like receptors (Cohen-Sfady et al. 2005 ). The group II chaperonin comprises archaeal thermosome (Phipps et al. 1991 (Phipps et al. , 1993 Andrä et al. 1996) and eukaryotic cytosolic chaperonin called CCT (chaperonin-containing TCP1) or TriC (TCP1 ring complex) (Frydman et al. 1992; Gutsche et al. 1999) . Members of this subfamily are composed of oligomeric eight-to nine-membered rings with each subunit weighing about~52-65 kDa (Frydman et al. 1992; Phipps et al. 1993; Andrä et al. 1996; Ditzel et al. 1998 ). Unlike group I members, members of group II chaperonins have a built-in lid that encapsulates the substrates within the central folding chamber upon ATP binding and does not require a general co-chaperonin for their folding activity (Ditzel et al. 1998; Meyer et al. 2003; Douglas et al. 2011) . The large oligomeric complex CCT is composed of two stacked identical rings of eight subunits (CCT1-8), each of which has a role in cytosolic protein folding and assembly through ATP hydrolysis (Bigotti and Clarke 2008) . After its discovery, the chaperoning role of CCT had been implicated in biogenesis of cytoskeletal proteins, β-actin and tubulin (Gao et al. 1992; Yaffe et al. 1992) .

A diverse range of functions of HSP60 in viral pathogenesis has been reported over the years. However, its immunomodulatory role has remained one of the most important and studied areas. The pro-viral effect of HSP60 in dengue virus infection is attributed to its elevated expression in infected human monocytic U-937 cells that leads to suppression of antiviral cytokine IFN-α (Padwad et al. 2009 ). HSP60 induces mitochondrial stress and enhances microglial production of pro-inflammatory cytokine IL-1β by activating NLRP3 inflammasome complex in Japanese encephalitis virus (JEV) infection (Swaroop et al. 2018) . Production of soluble HSP60 (sHSP60) has been reported from hepatitis B virus (HBV)infected replicating hepatocytes. sHSP60 enhances the frequency and function of HBcAg-specific interleukin-10 secreting regulatory T (T reg ) cells indicating the immunesuppressive role of sHSP60 (Kondo et al. 2010 ). Furthermore, this chaperonin is also involved in the regulation of apoptosis in viral pathogenesis. The anti-apoptotic nature of HSP60 is exemplified in hepatitis C virus (HCV) infection. Inactivation of HSP60 through its interaction with HCV core protein participates in the pathogenesis of HCV infection by induction of ROS generation and amplification of TNF-α-mediated cell death (Kang et al. 2009 ). HSP60 and co-chaperonin HSP10 together decrease the apoptotic potential of ectromelia virus-infected murine L929 fibroblasts by maintaining mitochondrial protein homeostasis, playing a role in altering the ratio of apoptotic proteins Bax, Bcl-2, and Bcl-xL (Wyżewski et al. 2019) . In contrast to the previous two cases, this chaperonin exerts a pro-apoptotic effect in case of rotavirus (RV) SA11 and HBV infection. mtHSP60 is tyrosine-phosphorylated by the activated form of Src kinase with its subsequent ubiquitin-mediated proteasomal degradation during the early hours of RV-SA11 infection. The proteasomal degradation of mtHSP60 is inversely correlated with premature mitochondrial import of rotaviral pro-apoptotic factor nonstructural protein 4 (NSP4) that further delays early apoptosis (Chattopadhyay et al. 2017) . In case of HBV infection also, the binding of HSP60 with hepatitis B virus X protein (HBx) has been shown to facilitate the HBx-mediated apoptosis (Tanaka et al. 2004 ). Viral infection and autoimmunity contribute to the pathogenesis of many autoimmune diseases. The molecular mimicry between viral antigens and host HSP60 is reported to be involved in the development of autoimmune diseases such as atherosclerosis and insulin-dependent diabetes mellitus (IDDM) or type 1 diabetes (T1D). The ability of the antibodies against human cytomegalovirus to cross-react with certain HSP60 epitopes that might amplify endothelial cell damage and the prevalence of these autoantibodies against HSP60 in most atherosclerotic patients have been correlated with the severity of this disease (Bason et al. 2003 ). The immunological cross-reaction between enterovirus capsid proteins and HSP60 of insulinproducing beta cells as autoantigens leads to destruction of these cells, playing a role in etiopathogenesis of IDDM (Härkönen et al. 2000) . Similarly, the molecular mimicry of glycoproteins E (gE) of varicella virus and hemagglutinin of measles virus with host HSP60, particularly in diabetics with genetic predisposition of HLA DR3/DR4, are also involved in etiopathology of T1D (Meziane et al. 2020) . Moreover, Ebola virus infection also induces secretion of autoantibodies against HSP60, which is a causative parameter of various serious autoimmune disorders observed in Ebola survivors (Fausther-Bovendo et al. 2017 ). In addition to previously mentioned functions, this chaperonin also interacts with other viral factors. HSP60 has also been identified as a chikungunya virus (CHIKV)-interacting protein that might play a role in CHIKV entry into the host cells (Wintachai et al. 2012) .

Similarly, HSP60 has been demonstrated to interact with human hepatitis B virus (HBV) polymerase that is important for maturation of this enzyme to active state (Park and Jung 2001) . Furthermore, HSP60 has also been demonstrated to be a part of stable RNA-protein complex consisting mur i n e h e p a t i t i s v i r u s ( M H V ) R N A a l o n g w i t h mitochondrial-aconitase, mitochondrial HSP70 and HSP40 (Nanda et al. 2004) .

Of the eight subunits of eukaryotic cytosolic chaperonin CCT, many have been reported to participate in the biological cycle of different viruses. The chaperonin TCP-1 (also known as CCT1) or a related protein has been reportedly associated with HBV core polypeptides in two different intermediates in viral assembly (Lingappa et al. 1994 ). CCT2 interacts with influenza virus RNA polymerase subunit PB2 where it is suggested to act as chaperone for PB2 and its incorporation into RNA polymerase complex (Fislová et al. 2010 ). The CCT3 aids in the proper folding of newly synthesized Gag polyprotein of Mason-Pfizer monkey virus (M-PMV) through its association with p4 and pp24/16-p12 domains of nascent Gag molecules. This further allows the intermolecular interactions between correctly folded Gag molecules for proper assembly of M-PMV capsid (Hong et al. 2001) . In case of neurotropic rabies virus (RABV) infection, CCT3 positively regulates intracellular viral replication after being recruited to Negri bodies with the help of a complex comprising viral N and P proteins ). The Epstein-Barr virus (EBV) encoded a nuclear and transformation-related protein, EBNA-3, showing an association with CCT5 for its initial folding (Kashuba et al. 1999) . CCT5 helps in the replication of hepatitis C virus (HCV) through its interaction with viral RNA polymerase NS5B ). The avian CCT5 has been demonstrated to bind with influenza A virus (IAV) nucleoprotein (NP) as well as polymerase basic protein 1 (PB1) and polymerase basic protein 2 (PB2). Moreover, the elevated expression of CCT5 benefits the viral infection by promoting nuclear export of NP as well as activity of the viral polymerase (Zhang et al. 2020) . The identification of CCT7 as a binding partner of the capsid protein hexon of Fowl adenovirus serotype 4 (FAdV-4) suggests its function in viral replication (Gao et al. 2019 ). The chaperonin CCT8 plays a role in the post-translocational refolding of tobamovirustransported proteins, thus facilitating the spread of viral infection (Fichtenbauer et al. 2012 ).

HSP60 has been co-purified with HIV virus preparation which suggests a specific association between this chaperone and viral factors encapsidated into HIV particles (Bartz et al. 1994) . Later, HSP60 was identified as an interacting partner of HIV transmembrane glycoprotein gp41 (Speth et al. 1999 ). The co-expression of two subunits of HIV-1 reverse transcriptase (HIV-1 RT) i.e. p66 and p55, with Escherichia coli chaperonin complex GroEL-GroES in E. coli, reportedly improved the yield and nucleic acid-binding activity of HIV-1 RT (Maier et al. 2000) . The human HSP60 has been demonstrated to interact with the catalytic core domain of HIV-1 integrase (IN) and is also able to stimulate the IN activity. Moreover, the viral IN was also recognized as a substrate by the functional human HSP60-HSP10 complex in presence of ATP (Parissi et al. 2001) . The level of circulating HSP60 has been found to be elevated in HIV-infected patients which was significantly reduced following anti-retroviral therapy (Anraku et al. 2012) . Furthermore, CCT5 also exhibited a strong association with HIV-1 p6 protein in the yeast two-hybrid system (Hong et al. 2001) .

Despite the extensive reports on function of HSP60 at different stages of viral pathogenesis, there have been limited studies on its role in HIV infection. Previously, mitochondrial stress has been reported in HIV infection (Pérez-Matute et al. 2013; Var et al. 2016 ) which raises the possibility of involvement of HSP60 in mitochondrial quality control during the course of infection. The function of HSP60 in immune modulation has also not been looked into in case of HIV infection. Though HIV-1 RT and gp41 have been identified as an interacting partner of this chaperonin, the functional significance of this association has remained unclear. Likewise, the binding of CCT5 with HIV-1 p6 protein has not been further characterized. Considering the well-studied roles of HSP60 and CCT in viral pathophysiology, future studies on the effect of the chaperonin system in HIV pathogenesis might be able to contribute significantly in this area.

The 70-kDa heat shock protein (HSP70) is one of the most conserved HSPs throughout the evolution, and its members are found in several intracellular compartments such as endoplasmic reticulum (HSPA5), mitochondria (HSPA9) and nucleus (HSPA1A and HSPA8). In unstressed cells, HSP70 forms 0.5 to 2% of the protein mass (Finka and Goloubinoff 2013) . Like most other HSPs, HSP70 is well established to function as a chaperone in protein folding, translocation, refolding and degradation (Finka et al. 2015a) . It is also known to interact with components of various signalling pathways, thereby affecting growth and development (Nollen and Morimoto 2002) . HSP70 is also well documented to play an anti-apoptotic role (Jäättelä et al. 1998 ). The HSP70 family has an N-terminal ATPase domain (nucleotide-binding domain) and a C-terminal substrate-binding domain. The C-terminal domain is subdivided into a β sandwich subdomain and a α helical subdomain (Mayer and Bukau 2005) (Fig. 2d) . The primary functions of HSP70 are dependent on its ATPase cycle. Normally, HSP70 is present in two states. One form is the ATP bound state that has low affinity for substrates and high substrate association and dissociation rates. The other form is the ADP-bound state that has high affinity for substrates but low substrate association and dissociation rates. The catalysis of ATP to ADP occurs through the low, intrinsic ATPase activity of HSP70. This activity is highly enhanced by HSP40 co-chaperones also called J domain proteins (JDP) (Minami et al. 1996) . The exchange of ADP with ATP is catalyzed by nucleotide exchange factors such as HSP110 and heat shock protein-binding protein (Bracher and Verghese 2015) .

HSP70 has 13 different isoforms in human cells that are found in several intracellular compartments. HSPA8 is a constitutive isoform, making up about 50% of the HSP70 family and found in the cytoplasm and nucleus (Finka and Goloubinoff 2013) . HSPA1A, an inducible member, is found in low amounts in unstressed cells. However, upon stress, an increase in HSPA1A makes it an abundant HSP70 isoform (Finka et al. 2015b ). HSPA1A is found on chromosome 6 in the major histocompatibility complex (MHC-III) region along with another identical heat-inducible HSP isoform called HSPA1B (Milner and Duncan Campbell 1990) . HSPA1L is found on the same chromosome 6 as HSPA1A and HSPA1B and is constitutively expressed in human testicular cells (Milner and Duncan Campbell 1990; Ito et al. 1998 ). HSPA5, found in the endoplasmic reticulum (Haas and Wabl 1983) , and HSPA9, found in the mitochondria (Domanico et al. 1993; Bhattacharyya et al. 1995) , form the next abundant members of the HSP70 family. HSPA6 (Leung et al. 1990 ) and HSPA7 (Voellmy et al. 1985) are highly similar, heat-inducible isoforms. HSPA12A and HSPA12B are distant members of the HSP70 family since they have an atypical ATPase domain. They were first found in the atherosclerotic lesions of mice (Han et al. 2003) . HSPA13 is a non-heat-inducible member of the HSP70 family expressed in all human cell types (Otterson and Kaye 1997) . HSPA14 is the last member of the HSP70 family and is found in dendritic cells and has enhanced Th1-polarizing activity (Wan et al. 2004) .

The change in expression and role of HSP70 in viral infections has been widely documented. Most of the earlier studies concentrated on the inducible HSP70 isoform HSPA1A (HSP72, HSPA1) and the constitutive isoform HSPA8 (HSC70, HSC71). For example, there is an increase in HSP70 levels during West Nile viral infection (Pastorino et al. 2009 ). HSC70 associates with and helps in folding of the capsid proteins of polyomavirus. This possibly prevents premature virion assembly and helps in the capsid translocation into the nucleus (Cripe et al. 1995; Chromy et al. 2003) . HSC70 is also involved in the life cycle of HPV at different steps of HPV DNA replication and is also required for nuclear localization of L2. HSC70 associates with L2 capsid protein of HPV as an intermediate for virus assembly (Florin et al. 2004) . It is also associated with the influenza virus matrix protein 1, which is important for virus replication, assembly and budding (Watanabe et al. 2006) . Studies show that HSP72 also interacts with NS5A, NS3 and NS5B replication proteins of HCV (Chen et al. 2010) . The role of the HSP70 family in HCV replication was corroborated by other studies in which quercetin was used to knock down HSP70 mRNA transcription that resulted in reduced HCV accumulation and particle production (Gonzalez et al. 2009 ). Vaccinia virus infection induces HSP70, and there is an association of HSP70 with viral proteins suggesting their involvement in virus assembly (Jindal and Young 1992) . Rabies virus infection also induces HSP70 expression, and HSP70 is required at different stages of the virus life cycle (Lahaye et al. 2012) . Recent studies show that the regulatory leader RNA of rabies virus interacts with HSC70 and downregulates virus replication (Zhang et al. 2017) .

Studies on the isoform-specific roles of HSP70 in viral infections were limited to the inducible HSP70 and constitutive HSC70 initially but have picked up in the last several years in roles of the other isoforms. For instance, filoviruses differentially exploit HSPA5. The mature virions of Ebola viruses contain HSPA5 whereas the Marburg viruses lack the presence of HSPA5 in the mature virions. Also, siRNA knockdown of HSPA5 reduces the cells infected with Ebola and Marburg virus. Further, knockdown also inhibits the release of new Ebola and Marburg virus particles (Spurgers et al. 2010; Patrick Reid et al. 2014) . HSPA5 is also implicated in several hepatitis virus infections. Hepatitis C virus non-structural protein 5A (NS5A) interacts with HSPA5 and enhances its expression in hepatocytes (Jiang et al. 2014) . HSPA5 is further reported to play an antiviral role in Hepatitis A virus infection (Jiang et al. 2017) . Human cytomegalovirus is another virus that induces HSPA5 transcription and translation (Buchkovich et al. 2008 (Buchkovich et al. , 2009 (Buchkovich et al. , 2010 . Taguwa et al. in 2015 showed the requirement of HSPA8 in the dengue virus life cycle such as in entry, RNA replication and virion biogenesis (Taguwa et al. 2015) . The same group showed that Zika virus depends on HSPA1A and HSPA8 to complete its life cycle (Taguwa et al. 2019) . In case of Enterovirus A71 virus infection, HSP70 isoforms such as HSPA1A, HSPA8 and HSPA9 are required at all steps of the virus life cycle (Su et al. 2020 ). In the current pandemic caused by SARS-CoV-2, early studies have suggested that HSPA5 is an important factor for the virus infection (Ha et al. 2020; Ibrahim et al. 2020) .

As is the case in most viral infections, the role of HSP70 in HIV-1 infection has been also analyzed to a great extent. A short study by Furlini et al. in 1993 indicated that there is nuclear translocation of HSP70 upon interaction between CD4+ and HIV-1 gp120. Also, the newly synthesized HSP70 is mainly derived from constitutively expressed mRNA stored in the cytoplasm (Furlini et al. 1994 ). HSP70 mRNA is upregulated in CD4+ T cells infected with HIV-1 (Wainberg et al. 1997) , and the expression of HSP70 is significantly increased in lymphocytes from HIV-1-infected subjects (Agnew et al. 2003 ). Later, it was shown that HSP70 is incorporated into HIV-1 virions and HIV-1 gag protein is sufficient for this phenomenon (Gurer et al. 2002) . However, the role of the incorporated HSP70 has not yet been elucidated in detail. It could be involved in the viral uncoating process post viral entry or it could bind to the nascent gag protein during transport to the plasma membrane. Recombinant M y c o b a c t e r i u m t u b e r c u l o s i s H S P 7 0 s h o w s a dose-dependent inhibition on HIV-1 infection of CD4+ T cells, and combining HSP70 with a monoclonal antibody to CCR5 showed a very high percentage of inhibition at 99.7% (+0.9%) (Babaahmady et al. 2007) . It is known that the tripartite motif 5α (TRIM5α) is a cellular protein that restricts HIV-1 at the early post-entry step (Nisole et al. 2005) . Further studies are needed to understand what role HSP70 plays in the TRIM5α restriction of HIV. A study in 2011 showed that Nef suppressed HSP70-mediated Tat activation and the suppressing effect is dependent on HSP70 expression (Sugiyama et al. 2011a) . The same group also showed that HSP70 inhibits the ubiquitination and degradation of APOBEC3G by Vif (Sugiyama et al. 2011b) . HSP70 also seems to be induced in HIV-infected cells to target HIV-1 Vpr and reduce Vpr-dependent G2 arrest and apoptosis (Iordanskiy et al. 2004b ). Iordanskiy et al. also showed that HSP70 stimulates nuclear import and replication in Vpr-deficient HIV-1 infected cells, basically taking over the function of Vpr. Interestingly, however, it has been reported to inhibit translocation of Vpr into the nucleus of wild-type infected cells (Iordanskiy et al. 2004a) .

The isoform-specific roles of HSP70 are being actively investigated in the past decade. In 2009, Bushman et al. released a meta-analysis of 9 different genome wide studies that were performed to identify common host factors involved in HIV-1 replication (Bushman et al. 2009 ). HSPA5 was noted to interact with the envelope protein during its folding in the endoplasmic reticulum (Earl et al. 1991) , and other isoforms were implicated to interact with viral proteins like Tat, Gag and Vpr. HIV-1 Clade B gp120 induces HSPA5 and other ER stress markers, as compared to HIV-1 Clade C gp120 in astrocytoma cells (López et al. 2017) . HIV-1 tat is also known to induce HSPA5 and other ER stress markers ). HSPA9 or mortalin was shown to be required for Nef secretion in exosomes (Shelton et al. 2012) . Independently, another group showed the interaction of HSPA9 and Nef through a yeast two-hybrid screen (Kammula et al. 2012) . A very systematic review of literature until December 2016 identifying various "candidate inhibitory factors" of HIV-1 infection was published in 2018 (Gélinas et al. 2018) . Several HSP40, HSP70 and HSP90 isoforms were implicated in different stages of the virus life cycle. While the role of HSP70 isoforms in HIV-1 infection is better characterized than other HSP families, it still needs to be fully explored. For example, while HSPA8 has been indicated to play vital roles in replication and viral assembly in other viral infections, its role in HIV-1 infection remains to be clearly elucidated. In another instance, HSPA2 and HSPA1L have not been characterized either in other viral infections or in HIV-1 infection. Due to their enrichment in testis tissue, they may play a vital role in HIV-1 entry. Added to that, the direct roles of the distant HSP70 members HSPA12, HSPA13 and HSPA14 in HIV-1 infection have not at all been looked into, even though HSPA13 was shown to possibly interact with the Env protein (Luo et al. 2016) . Another aspect that needs to be understood is the implication of HSP70-HSP40-HSP90 interactions during HIV-1 infection.

HSP90 (heat shock protein, 90 kDa) is a vital, evolutionarily conserved and the most abundant member of the HSP family, making up to 1-2% of the total cellular proteins (Csermely et al. 1998) . Unlike other members of the HSP family, HSP90 interacts with specific classes of substrates which majorly comprises kinases and steroid hormone receptors (Riggs et al. 2004) . Dimerization of HSP90 is vital for its essential ATPase activity where each monomer consists of an N-terminal nucleotide-binding domain, a middle domain that binds to the client proteins and a C terminal dimerization domain (Schopf et al. 2017) (Fig. 2e) . In the cytoplasm, HSP90 is expressed as stress-inducible isoform HSP90α that includes two transcript variants i.e. HSP90AA1 and HSP90AA2, and one constitutive isoform HSP90AB1/ HSP90β. These cytosolic isoforms are involved in the activity, maturation, stabilization and turnover of a huge set of substrates (Stechmann and Cavalier-Smith 2004; Chen et al. 2005; Zuehlke et al. 2015) . Other than the cytosolic variants, one HSP90 isoform is present in endoplasmic reticulum (ER) as HSP90B1 (other names are endoplasmin, Grp94, gp96, TRA1) and one in mitochondria as tumour necrosis factor receptor-associated protein-1 (TRAP1) (Ho Yeong Song et al. 1995; Stechmann and Cavalier-Smith 2004; Chen et al. 2005) . Apart from being a peptide-binding protein, HSP90B1 is also important in Ca 2+ homeostasis, ER stress response and host defence (Randow and Seed 2001; Eletto et al. 2010) . TRAP1 is known for its role in protection against oxidative stress and apoptosis (Masuda et al. 2004; Hua et al. 2007; Im et al. 2007) .

HSP90 has been known to play a role in viral protein folding for several different viruses. The chaperone activity of HSP90 is also important for maturation and maintenance of viral proteins including polymerases, capsids and cell attachment factors through interaction. This behaviour is exemplified by the role of HSP90 in folding of viral L polymerase in measles and Nipah virus (Bloyet et al. 2016) , as well as in stabilization of the L protein in La Crosse virus (Connor et al. 2007) , mumps virus (Katoh et al. 2017 ) and vesicular stomatitis virus (Connor et al. 2007) . It participates in capsid precursor processing and capsid assembly of picornaviruses, including coxsackievirus, poliovirus and rhinovirus (Geller et al. 2007 ). The chaperone is reportedly involved in biogenesis of reovirus cell attachment factor σ1 (Gilmore et al. 1998 ). In addition to its well-known chaperoning machinery, it is also important for activity of reverse transcriptase of hepatitis B virus and NS2/3 protease of hepatitis C virus (Hu and Seeger 1996; Hu et al. 1997; Hu and Anselmo 2000; Waxman et al. 2001) . Furthermore, HSP90 is required for the proper localization of DNA polymerase of herpes simplex virus (Burch and Weller 2005) and intracellular transportation of the RNA polymerase of influenza virus (Naito et al. 2007 ) and viral capsids in early hepatitis E virus infection (Zheng et al. 2010 ). HSP90 has been found to be a part of receptor complex in dengue virus entry (Reyes-del Valle et al. 2005) . Moreover, HSP90 participates in the replication cycle of multiple other virus families such as Bimaviridae ), Filoviridae (Smith et al. 2010) , Polyomaviridae (Miyata and Yahara 2000) and Togaviridae (Rathore et al. 2014) . A recent large-scale transcriptomics profiling of cells infected with SARS-CoV-2 identified HSP90 as important for infection. Inhibition of HSP90 activity caused reduction in viral replication and proinflammatory response Wyler et al. 2021) . In Avibirnavirus infection, HSP90AA1 triggers autophagy by AKT-mTOR-dependent pathway upon pathogen recognition which is a crucial step in controlling the pathogenesis (Hu et al. 2015) . The HSP90AA1 machinery is involved in maintaining stability of rabies virus phosphoprotein (Xu et al. 2016) . The ER-predominant HSP90B1 is also released in extracellular space and is taken up by antigen-presenting cells (APCs) in case of vaccinia virusinduced cell lysis (Berwin et al. 2001 ). This isoform is critical in antigen cross-presentation in long-lived lymphocytic choriomeningitis virus infection (Basta et al. 2005) . Inhibition of HSP90B1 also inhibits replication of flaviviruses including dengue virus and Zika virus (Rothan et al. 2019) . HSP90 has been also reported as a possible anti-viral target in a number of studies .

Considering the diverse range of cellular function of HSP90, we still have limited knowledge on its role in the area of HIV research. HSP90 has been reported to positively regulate HIV-1 gene expression in acutely infected cells and localize on the viral promoter which might directly control viral transcription (Vozzolo et al. 2010) . Another study has shown that the phenomenon of HSP90 co-localization with actively transcribing provirus is enhanced in hyperthermic conditions leading to increase in HIV-1 replication (Roesch et al. 2012) . Recently, we have reported that the LTR-driven gene expression is enhanced and suppressed by over-expression and silencing of HSP90 respectively in HEK293T cells and novel HSP90 inhibitors can suppress virus replication, indicating its possible use as a therapeutic target (Trivedi et al. 2019) . Like other elements of heat shock pathway namely heat shock factor-1 (HSF-1), HSP90 also governs HIV-1 reactivation from latent reservoirs present in resting host cells (Timmons et al. 2020) . HSP90 regulates NF-κB pathway that connects T-cell activation with viral replication, thereby contributing to proviral reactivation (Anderson et al. 2014) . Quiescence induced by inhibition of HSP90 in human hematopoietic stem and progenitor cells (HSPCs) makes them susceptible to predominantly latent HIV-1 infection (Painter et al. 2017) . By proteasome inhibition, HSP90 facilitates the latent reactivation process by maintaining positive transcription elongation factor b (p-TEFb) functional, which in turn indicates the role of HSP90 in viral transcriptional elongation (Pan et al. 2016) . In primary T cells, inhibition of HSP90 blocks p-TEFb assembly which suppresses the reactivation from HIV-1 latency (Mbonye et al. 2018) . Another study has also shown that pan-histone deacetylase inhibitors (HDIs) are less effective than the class 1-selective HDIs in mediating viral reactivation due to more off-target inhibition of cellular factors like HSP90 which are crucial for optimal HIV transcription (Zaikos et al. 2018) . HSP90AA1 is reportedly involved in HIV-1 reactivation and has also been predicted to play an important role in HIV-associated encephalitis pathogenesis (Shityakov et al. 2015) . In addition to its role in HIV-1 replication and reactivation, HSP90 contributes to the infectivity of progeny virus. The cytosolic isoform HSP90AB1 can rescue infectivity of ritonavir-resistant virus particles impaired by accumulation of the capsid-spacer peptide 1 (CA-SP1) precursor in HIV-1 (Joshi and Stoddart 2011) . The same group further showed that HSP90AB1 is also present in virions outside the core and restores infectivity of HIV-1 particles with mutated capsid proteins (Joshi et al. 2013) . Since viral antigens bound to HSPs are known to augment antiviral immunity, few studies have demonstrated how HSP90B1 can be used as an adjuvant to enhance cellular and humoral immune responses against HIV-1 infection (Gong et al. 2009; Kadkhodayan et al. 2017) . Knockdown of HSP90B1 also causes a significant increase in expression of the CD4 receptor in HIV-1-infected SupT1 T-cells (Landi et al. 2014) . Based on all of the above, one can speculate that it will be interesting to elucidate the role of non-cytosolic HSP90 isoforms in virus infection.

The literature on the HSP110 (also termed as HSP105) family is the most limited. HSP110 is part of the HSP70 superfamily. It is related to the HSP70 family, but its ATPase domain is more divergent and the C-terminal domain is of varying lengths. There is also the presence of a long loop-like structure between the β sandwich subdomain and the α helical subdomain (Lee-Yoon et al. 1995; Easton et al. 2000) (Fig.  2f) . The HSP110 family is the third most abundant heat shock protein family. In heat shocked CHO cells, HSP110 forms 0.7% of the total cellular proteins (Subjeck et al. 1982) . The family consists of isoforms other than HSPH1 (HSP105, HSP110) as well. The 170-kDa glucose regulatory protein HSPH4 (GRP170) is a related member that resides in the endoplasmic reticulum of the cell. It consists of an ATP-binding domain and an NDEL sequence in the carboxy-terminal domain (Chen et al. 1996) . Another isoform is HSPH3 (APG1), an isoform that is expressed constitutively in testis germ cells (Kaneko et al. 1997 ). Yet another isoform that comes under the HSP110 family is HSPH2 (APG2), which seems to be required for cytoplasm to vacuole targeting, autophagy and pexophagy pathways (Wang et al. 2001a) . The genes of both human HSPH2 and HSPH3 were cloned from a human testis cDNA library. In human endothelial cells, APG1 transcripts and not APG2 transcripts was induced by a rise in temperature from 32°C temperature to 39°C (Nonoguchi et al. 1999) .

The HSP110 family also acts as nucleotide exchange factors for the HSP70 family. It was first shown that the yeast HSP110, Sse1, interacts with the yeast HSP70 chaperones, Ssa and Ssb (Shaner et al. 2005) . Using the yeast homologue, Polier et al. provided a structural basis of the nucleotide exchange on HSP70 catalyzed by HSP110, thereby releasing the bound ADP after one cycle of HSP70-driven ATP hydrolysis (Polier et al. 2008 ). Thus, it performs the role of molecular chaperone. Apart from its chaperone role, HSP110 is widely studied for its other roles in the cell. HSP110 has been investigated as a potential vaccine candidate in the phase I trial for cancer therapeutics as it was shown to induce the tumour-specific cytotoxic T lymphocyte response (Wang et al. 2001b; Shimizu et al. 2019 ). Overexpression of HSP110 (APG2 or HSPH2) may also correspond to earlier recurrence of cancer (Yang et al. 2015) . HSP110 is also documented to have a critical role on the cardio-vascular system where it associates with endothelial nitric oxide synthase and induces dilations of the blood vessels (Benjamin and McMillan 1998) . Recently, it was also demonstrated that upon genotoxic stress conditions, HSP110 translocates into the nucleus and induces the repair of damaged DNA both in vitro as well as in vivo (Causse et al. 2019) . Additionally, HSP110 is crucial for spindle assembly checkpoint activation in case of heat shock-induced cell cycle arrest (Kakihana et al. 2019) . Further, HSP110 is also shown to reduce the aggregation of alpha-synuclein and has positive impact on Parkinson's disease (Taguchi et al. 2019) .

In case of virus infection, unlike other HSPs, the detailed role of HSP110 is yet to be characterized. However, few studies have shown significant modulation of HSP110 and its consequences on virus infection and host immune response. In case of flavivirus infections, HSP110 induces the virus-specific T-cell response in vitro; however, this enhancement is not observed in case of in vivo studies (McLaughlin et al. 2011) . A critical step in the SV40 infection cycle is the penetration by the non-enveloped virus of the endoplasmic reticulum membrane to reach the cytosol. HSPH1 (HSP105) enables this by interacting with the ER DNAJB14 and cooperating with HSPA8 (Ravindran et al. 2015) . A direct role for the other isoform of the HSP110 family, HSPH2 (APG2) in viral infections has not yet been delineated. However, a recent paper showed that APG2 shows up in a network of proteins connected to ACE2, a protein that is seemingly important for the SARS-CoV-2 virus entry. This is important because APG2 is a target for several drugs (Cava et al. 2020) . HSPH2 (APG2) and not HSPH3 (APG1) is upregulated in Hepatitis B virus-related early stage hepatocellular carcinoma. HSPH3 (APG1/HSPA4L), on the other hand, is modulated by the Spanish flu virus that caused the 1918 pandemic as well as by the reassortant viruses of the 1918 influenza virus and human H1N1 virus (Watanabe et al. 2013 ). HSPH4 (GRP170) was shown to associate with viral interleukin-6 (vIL-6), encoded by human herpes virus (Giffin et al. 2014) . In another instance, Khachatoorian et al. reviewed several studies documenting the increase in the expression of HSP110 upon Hepatitis C virus (HCV) infection (Khachatoorian and French 2016) . Although substantial evidences indicate the role of HSP110 in association with HSP40 and HSP70, the direct role of HSP110 is yet to be elucidated in case of HIV and other virus infections.

The review highlights the presence of both highly diverse and conserved heat shock proteins (HSPs) inside the cells that help to maintain a general cellular homeostasis, and are also modulated during stress conditions. These proteins are classified into various families based on their molecular weights. Furthermore, present literature shows that each family comprises several isoforms. These proteins are widely distributed throughout the cellular compartments such as the cytoplasm, nucleus, endoplasmic reticulum and mitochondria, and some of the isoforms are compartment specific; for example, TRAP1 of the HSP90 family is located primarily in the mitochondria as is HSPA9 of the HSP70 family. The presence, diversity and localization of these isoforms suggest specific roles for them. Roles for some of these isoforms have been delineated in cancer, viral infection and other diseases, but a lot of it still remains to be elucidated.

With limited resources, viruses are unable to infect, propagate and produce functional virus progeny in the host on their own. Thus, viruses hijack the cellular machinery that also enables them to evade from the host immune response. In case of HIV-1, viral replication, the latency and reactivation of latent provirus is largely regulated by a variety of host factors. Cellular heat shock family proteins have been identified as the host proteins with plethora of functions in case of HIV infection and pathogenesis. However, an elaborate study on the isoform-specific role of HSPs in case of HIV and other virus

infections is yet to be elucidated, although progress has been made on some fronts as highlighted in this review. In case of sHSPs, out of 10 isoforms, only 4 are characterized to a limited extent in HIV-1 infection. Similar gaps exist in the studies on the role of CCT. While different subunits of the CCT complex have been reported to participate in other virus life cycles, there is only limited information on their role during HIV infection. The literature on HSP40 also presents the same lacunae. The family's highly diverse nature is indicative of specialized functions possibly in both cellular homeostasis and disease conditions. Further investigations will have to be carried out to understand the specific roles of each of the isoform in HIV-1 infection. The current pandemic caused due to SARS-CoV-2 has further highlighted the importance of HSPs in viral infections. For example, chaperones such as HSP60, HSP70 and HSP90 are immunogenically similar to certain SARS-CoV-2 proteins, leading to cases of molecular In this graphical presentation, the members of different HSP families are presented at different stages of the virus life cycle labelled as (1) attachment, (2) entry, (3) uncoating, (4) nuclear import, (5) replication or transcription, (6) translation and protein folding, (7) assembly and (8) virion release. This comparative presentation indicates isoforms reported to be involved in other virus' life cycle and in HIV-1 infection mimicry. Cross-reactive antibodies produced after infection can cause the body to attack self, leading to some of the pathological manifestations seen in COVID-19 (Paladino et al. 2020; Kasperkiewicz 2021) . Figure 3 shows that while more studies have been performed in understanding the role of various isoforms in different steps of the life cycle of other viruses, much remains to be studied and elucidated in case of HIV-1 infection. Furthermore, these studies may enable us to develop specific therapeutic strategies to control the virus spread and AIDS pathogenesis. Thus, it becomes imperative to study and understand the role of specific HSP isoforms and their interaction with other proteins during different stress conditions including virus infection.

Altered lymphocyte heat shock protein 70 expression in patients with HIV disease

Positive selection in autoimmunity: abnormal immune responses to a bacterial dnaJ antigenic determinant in patients with early rheumatoid arthritis

Heat shock protein 90 controls HIV-1 reactivation from latency

Purification and structural characterization of the thermosome from the hyperthermophilic archaeum Methanopyrus kandleri

Circulating heat shock protein 60 levels are elevated in HIV patients and are reduced by anti-retroviral therapy

Hsp27: Novel regulator of intracellular redox state

Cytotoxic effects induced by oxidative stress in cultured mammalian cells and protection provided by Hsp27 expression

Inhibition of human immunodeficiency virus type 1 infection of human CD4+ T cells by microbial HSP70 and the peptide epitope 407-426

Regulation of Sam68 activity by small heat shock protein 22

An Hsp60 related protein is associated with purified HIV and SIV

Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis

Cross-presentation of the long-lived lymphocytic choriomeningitis virus nucleoprotein does not require neosynthesis and is enhanced via heat shock proteins

Hepatitis B virus replication

Efficient Hsp90-independent in vitro activation by Hsc70 and Hsp40 of duck hepatitis B virus reverse transcriptase, an assumed Hsp90 client protein

Heat-shock proteins as molecular chaperones

Molecular chaperones in cardiovascular biology and disease

Virally induced lytic cell death elicits the release of immunogenic GRP94/gp96

Cloning and subcellular localization of human mitochondrial hsp70

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive

Chaperonins: the hunt for the Group II mechanism

HSP90 chaperoning in addition to phosphoprotein required for folding but not for supporting enzymatic activities of measles and Nipah virus L polymerases

The nucleotide exchange factors of Hsp70 molecular chaperones

The crystal structure of the bacterial chaperonln GroEL at 2.8 Å

Altered constitutive and stress-regulated heat shock protein 27 expression in HIV type 1-infected cell lines

Heat shock protein-based therapeutic strategies against human immunodeficiency virus type infection

Hsp27 negatively regulates cell death by interacting with cytochrome c

The endoplasmic reticulum chaperone BiP/GRP78 is important in the structure and function of the human cytomegalovirus assembly compartment

Human cytomegalovirus specifically controls the levels of the endoplasmic reticulum chaperone BiP/GRP78, which is required for virion assembly

Human cytomegalovirus induces the endoplasmic reticulum chaperone BiP through increased transcription and activation of translation by using the BiP internal ribosome entry site

Herpes simplex virus type 1 DNA polymerase requires the mammalian chaperone Hsp90 for proper localization to the nucleus

Host cell factors in HIV replication: meta-analysis of genome-wide studies

DnaJA1/Hsp40 is co-opted by influenza A virus to enhance its viral RNA polymerase activity

HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells

In silico discovery of candidate drugs against covid-19

Comparative analysis of differential gene expression of HSP40 and HSP70 family isoforms during heat stress and HIV-1 infection in T-cells

The interaction of HSP27 with Daxx identifies a potential regulatory role of HSP27 in Fas-induced apoptosis

Tyrosine phosphorylation modulates mitochondrial chaperonin Hsp60 and delays rotavirus NSP4-mediated apoptotic signaling in host cells

Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function

The HSP90 family of genes in the human genome: Insights into their divergence and evolution

Location of a folding protein and shape changes in GroEL-GroES complexes imaged by cryoelectron microscopy

The 170 kDa glucose regulated stress protein is a large HSP70-, HSP110-like protein of the endoplasmic reticulum

Heat shock protein 72 is associated with the hepatitis C virus replicase complex and enhances viral RNA replication

HTLV-1 Tax-associated hTid-1, a human DnaJ protein, is a repressor of IκB kinase β subunit

Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria

Hsp40 facilitates nuclear import of the human immunodeficiency virus type 2 Vpx-mediated preintegration complex

The growth transformation of human B cells involves superinduction of hsp70 and hsp90

Large isoform of mammalian relative of dnaJ is a major determinant of human susceptibility to HIV-1 infection

Chaperone-mediated in vitro assembly of polyomavirus capsids

Isolation of an IgG monoclonal anti-dnaJ antibody

Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway

Heat shock protein 60, via MyD88 innate signaling, protects B cells from apoptosis, spontaneous and induced

Antiviral activity and RNA polymerase degradation following Hsp90 inhibition in a range of negative strand viruses

High affinity binding between Hsp70 and the C-terminal domain of the measles virus nucleoprotein requires an Hsp40 co-chaperone

In vivo and in vitro association of hsc70 with polyomavirus capsid proteins

The 90-kDa molecular chaperone family: structure, function, and clinical applications. A Comprehensive Review

Hsp27 Responds to and facilitates enterovirus A71 replication by enhancing viral internal ribosome entry site-mediated translation

Illustration of HIV-1 protease folding through a molten-globule-like intermediate using an experimental model that implicates α-crystallin and calcium ions

JDP1 (DNAJC12/Hsp40) expression in breast cancer and its association with estrogen receptor status

Surface expressed heat-shock proteins by stressed or human immunodeficiency virus (HIV)-infected lymphoid cells represent the target for antibodydependent cellular cytotoxicity

Crystal structure of the thermosome, the archaeal chaperonin and homolog of CCT

Cloning of the gene encoding peptide-binding protein 74 shows that it is a new member of the heat shock protein 70 family

Dual action of ATP hydrolysis couples lid closure to substrate release into the group II chaperonin chamber

The role of molecular chaperones in spermatogenesis and the post-testicular maturation of mammalian spermatozoa

Folding, interaction with GRP78-BiP, assembly, and transport of the human immunodeficiency virus type 1 envelope protein

The Hsp110 and Grp170 stress proteins: newly recognized relatives of the Hsp70s

GRP94 in ER quality control and stress responses

Mechanisms for regulation of Hsp70 function by Hsp40

Ebola virus infection induces autoimmunity against dsDNA and HSP60

Heat-shock proteins, molecular chaperones, and the stress response: Evolutionary and ecological physiology

Stressed apoptotic tumor cells stimulate dendritic cells and induce specific cytotoxic T cells

The chaperonin CCT8 facilitates spread of tobamovirus infection

Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis

Multi-layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones

Quantitative proteomics of heat-treated human cells show an acrossthe-board mild depletion of housekeeping proteins to massively accumulate few HSPs

Association of the influenza virus RNA polymerase subunit PB2 with the host chaperonin CCT

Nuclear translocation of papillomavirus minor capsid protein L2 requires Hsc70

Function in protein folding of TRiC, a cytosolic ring complex containing TCP-1 and structurally related subunits

Human immunodeficiency virus type 1 interaction with the membrane of CD4+ cells induces the synthesis and nuclear translocation of 70 K heat shock protein

Identification of the phosphorylation sites of the murine small heat shock protein hsp25

Requirement of cellular protein CCT7 for the replication of fowl adenovirus serotype 4 (FAdV-4) in leghorn male hepatocellular cells via interaction with the viral hexon protein

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive

A cytoplasmic chaperonin that catalyzes β-actin folding

Multiple inhibitory factors act in the late phase of HIV-1 replication: a systematic review of the literature

Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance

Role of the major heat shock proteins as molecular chaperones

Modulation of Kaposi's sarcoma-associated herpesvirus interleukin-6 function by hypoxiaupregulated protein 1

Active participation of Hsp90 in the biogenesis of the trimeric reovirus cell attachment protein σ1

Activation of heat-shock response by an adenovirus is essential for virus replication

Glycoprotein 96-mediated presentation of human immunodeficiency virus type 1 (HIV-1)-specific human leukocyte antigen class I-restricted peptide and humoral immune responses to HIV-1 p24

The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production

BiP and multiple DNAJ molecular chaperones in the endoplasmic reticulum are required for efficient simian virus 40 infection

Interaction of Hsp40 with influenza virus M2 protein: Implications for PKR signaling pathway

Regulation of actin filament dynamics by p38 map kinasemediated phosphorylation of heat shock protein 27

Specific incorporation of heat shock protein 70 family members into primate lentiviral virions

Group II chaperonins: New TRiC(k)s and turns of a protein folding machine

The stress-inducible molecular chaperone GRP78 as potential therapeutic target for coronavirus infection

Immunoglobulin heavy chain binding protein

Two Hsp70 family members expressed in atherosclerotic lesions

Picornavirus proteins share antigenic determinants with heat shock proteins 60/65

Hsp27 inhibits Bax activation and apoptosis via a phosphatidylinositol 3-kinase-dependent mechanism

Homologous plant and bacterial proteins chaperone oligomeric protein assembly

Purification and properties of groE, a host protein involved in bacteriophage assembly

Identification of a protein with homology to hsp90 that binds the type 1 tumor necrosis factor receptor

Isolation and characterization of the host protein groE involved in bacteriophage lambda assembly

Type D retrovirus Gag polyprotein interacts with the cytosolic chaperonin TRiC

α-Crystallin can function as a molecular chaperone

Binding of the pathogen receptor HSP90AA1 to avibirnavirus VP2 induces autophagy by inactivating the AKT-MTOR pathway

In vitro reconstitution of a functional duck hepatitis B virus reverse transcriptase: posttranslational activation by Hsp90

Hepadnavirus assembly and reverse transcription require a multi-component chaperone complex which is incorporated into nucleocapsids

Hsp90 is required for the activity of a hepatitis B virus reverse transcriptase

Heat shock protein 75 (TRAP1) antagonizes reactive oxygen species generation and protects cells from granzyme M-mediated apoptosis

COVID-19 spike-host cell receptor GRP78 binding site prediction

Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor-associated protein 1 (TRAP1) regulates production of reactive oxygen species

Chaperonin TRiC/CCT participates in replication of hepatitis C virus genome via interaction with the viral NS5B protein

Heat-shock protein 70 exerts opposing effects on Vprdependent and Vpr-independent HIV-1 replication in macrophages

Heat shock protein 70 protects cells from cell cycle arrest and apoptosis induced by human immunodeficiency virus type 1 viral protein R

Genomic structure of the spermatid-specific Hsp70 homolog gene located in the class III region of the major histocompatibility complex of mouse and man

Hsp7O exerts its anti-apoptotic function downstream of caspase-3-like proteases

Glucose-regulated protein 78 is an antiviral against hepatitis a virus replication

Hepatitis C virus nonstructural protein 5A inhibits thapsigargin-induced apoptosis

Vaccinia virus infection induces a stress response that leads to association of Hsp70 with viral proteins

Heat shock protein 90AB1 and hyperthermia rescue infectivity of HIV with defective cores

Impaired infectivity of ritonavir-resistant HIV is rescued by heat shock protein 90AB1

Combination of cell penetrating peptides and heterologous DNA prime/protein boost strategy enhances immune responses against HIV-1 Nef antigen in BALB/c mouse model

Heat shock-induced mitotic arrest requires heat shock protein 105 for the activation of spindle assembly checkpoint

Brain transcriptome-wide screen for HIV-1 Nef protein interaction partners reveals various membrane-associated proteins

The HSP70 chaperone machinery: J proteins as drivers of functional specificity

Guidelines for the nomenclature of the human heat shock proteins

A novel hsp110-related gene, apg-1, that is abundantly expressed in the testis responds to a low temperature heat shock rather than the traditional elevated temperatures

Interaction of hepatitis C virus core protein with Hsp60 triggers the production of reactive oxygen species and enhances TNFα-mediated apoptosis

Epstein-Barr virus-encoded nuclear protein EBNA-3 interacts with the ε-subunit o f the T-complex, protein 1 chaperonin complex

Covid-19, heat shock proteins, and autoimmune bullous diseases: a potential link deserving further attention

Heat shock protein 90 ensures efficient mumps virus replication by assisting with viral polymerase complex formation

Chaperones in hepatitis C virus infection

Crystal structure of a small heat-shock protein

αBcrystallin is a small heat shock protein

The host heat shock protein MRJ/ DNAJB6 modulates virus infection

Herpes simplex virus-induced expression of 70 kDa heat shock protein (HSP70) requires early protein synthesis but not viral DNA replication

Inhibition of NF-κB activity by HIV-1 Vpr is dependent on Vpr binding protein

Hepatitis B virus replication could enhance regulatory T cell activity by producing soluble heat shock protein 60 from hepatocytes

Heat shock protein 40 is necessary for human immunodeficiency virus-1 Nef-mediated enhancement of viral gene expression and replication

Reciprocal regulation of human immunodeficiency virus-1 gene expression and replication by heat shock proteins 40 and 70

Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor

Hsp70 protein positively regulates rabies virus infection

Genome-wide shRNA screening identifies host factors involved in early endocytic events for HIV-1-induced CD4 down-regulation

Human HSP27 is phosphorylated at serines Diversity in heat shock protein families: functional implications in virus infection with a comprehensive

Chaperones and protein folding in the archaea

Activation of the herpes simplex virus type-1 origin-binding protein (UL9) by heat shock proteins

Heat shock proteins in neurodegenerative disorders and aging

Identification of a major subfamily of large hsp70-like proteins through the cloning of the mammalian 110-kDa heat shock protein

Self-association and chaperone activity of Hsp27 are thermally activated

The human heat-shock protein family: expression of a novel heatinducible HSP70 (HSP70B') and isolation of its cDNA and genomic DNA

Human coronavirus dependency on host heat shock protein 90 reveals an antiviral target

Chaperone proteins abrogate inhibition of the human papillomavirus (HPV) E1 replicative helicase by the HPV E2 protein

Chicken heat shock protein 90 is a component of the putative cellular receptor complex of infectious bursal disease virus

Cellular Hsp27 interacts with classical swine fever virus NS5A protein and negatively regulates viral replication by the NF-κB signaling pathway

A eukaryotic cytosolic chaperonin is associated with a high molecular weight intermediate in the assembly of hepatitis B virus capsid, a multimeric particle

Human Hsp70 and Hsp40 chaperone proteins facilitate human papillomavirus-11 E1 protein binding to the origin and stimulate cell-free DNA replication

HIV-1 Gp120 clade B/C induces a GRP78 driven cytoprotective mechanism in astrocytoma

HIV-host interactome revealed directly from infected cells

HIV Tat-mediated induction of human brain microvascular endothelial cell apoptosis involves endoplasmic reticulum stress and mitochondrial dysfunction

Association of heat shock protein 70 with enterovirus capsid precursor P1 in infected human cells

The Hsp60 folding machinery is crucial for manganese superoxide dismutase folding and function

Effect of Escherichia coli chaperonin GroELS on heterologously expressed human immunodeficiency virus type 1 reverse transcriptase in vivo and in vitro

Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation

Involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in apoptosis induced by β-hydroxyisovalerylshikonin

Modification and reorganization of the cytoprotective cellular chaperone Hsp27 during herpes simplex virus type 1 infection

Gymnastics of molecular chaperones

Hsp70 chaperones: cellular functions and molecular mechanism

Cyclin-dependent kinase 7 (CDK7)-mediated phosphorylation of the CDK9 activation loop promotes P-TEFb assembly with Tat and proviral HIV reactivation

Hsp110-mediated enhancement of CD4+ T cell responses to the envelope glycoprotein of members of the family Flaviviridae in vitro does not occur in vivo

Large unphosphorylated aggregates as the active form of hsp27 which controls intracellular reactive oxygen species and glutathione levels and generates a protection against TNFα in NIH-3T3-ras cells

The molecular chaperone hsp40 regulates the activity of P58IPK, the cellular inhibitor of PKR

Closing the folding chamber of the eukaryotic chaperonin requires the transition state of ATP hydrolysis

Molecular mimicry between varicella, measles virus and Hsp60 in type 1 diabetes associated HLA-DR3/DR4 molecules

Small heat shock protein 27: An effective adjuvant for enhancement of HIV-1 Nef antigen-specific immunity

The effects of heat shock proteins on delivery of HIV-1 Nef antigen in mammalian cells

Heat shock proteins regulatory role in neurodevelopment

Structure and expression of the three MHC-linked HSP70 genes

Regulation of the heat-shock protein 70 reaction cycle by the mammalian DnaJ homolog, Hsp40

Multi-faceted role of HSP40 in cancer

p53-independent association between SV40 large T antigen and the major cytosolic heat shock protein, HSP90

Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils

Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits

Mitochondrial HSP70, HSP40, and HSP60 bind to the 3′ untranslated region of the Murine hepatitis virus genome

Molecular chaperones in pathogen virulence: emerging new targets for therapy

Induction of the synthesis of a 70,000 dalton mammalian heat shock protein by the adenovirus E1A gene product

TRIM family proteins: retroviral restriction and antiviral defence

Chaperoning signaling pathways: molecular chaperones as stress-sensing "heat shock" proteins

Cloning of human cDNAs for Apg-1 and Apg-2, members of the Hsp110 family, and chromosomal assignment of their genes

Cutting edge: heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex

Trinucleotide repeat disorders

Protein folding in mitochondria requires complex formation with hsp60 and ATP hydrolysis

A "core ATPase

RNA interference mediated silencing of Hsp60 gene in human monocytic myeloma cell line U937 revealed decreased dengue virus multiplication

Quiescence promotes latent HIV infection and resistance to reactivation from latency with histone deacetylase inhibitors

The role of molecular chaperones in virus infection and implications for understanding and treating COVID-19

Heat shock protein 90 facilitates latent HIV reactivation through maintaining the function of positive Transcriptional Elongation Factor b (p-TEFb) under proteasome inhibition

Functional interactions of human immunodeficiency virus type 1 integrase with human and yeast HSP60

Human hepatitis B virus polymerase interacts with the molecular chaperonin Hsp60

The role of heat-shock proteins in thermotolerance

Identification of cellular proteome modifications in response to West Nile virus infection

HSPA5 is an essential host factor for Ebola virus infection

Role of mitochondria in HIV infection and associated metabolic disorders: focus on nonalcoholic fatty liver disease and lipodystrophy syndrome

A novel ATPase complex selectively accumulated upon heat shock is a major cellular component of thermophilic archaebacteria

Structure of a molecular chaperone from a thermophilic archaebacterium

Roles of the heat shock transcription factors in regulation of the heat shock response and beyond

Different expression of CD44, ICAM-1, and HSP60 on primary tumor and metastases of a human pancreatic carcinoma growing in scid mice

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive

Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding

The diversity of the DnaJ/ Hsp40 family, the crucial partners for Hsp70 chaperones

Heat shock protein 27 mediated signaling in viral infection

Vilariño-Güell C (2015) VPS35 and DNAJC13 disease-causing variants in essential tremor

Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability

Chikungunya virus nsP3 & nsP4 interacts with HSP-90 to promote virus replication: HSP-90 inhibitors reduce CHIKV infection and inflammation in vivo

A non-enveloped virus hijacks host disaggregation machinery to translocate across the endoplasmic reticulum membrane

Heat shock protein 90 and heat shock protein 70 are components of Dengue virus receptor complex in human cells

Functional specificity of co-chaperone interactions with Hsp90 client proteins

A new puffing pattern induced by temperature shock and DNP in drosophila

Hyperthermia stimulates HIV-1 replication

Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor by phosphorylation

Small molecule grp94 inhibitors block dengue and Zika virus replication

Chaperone machines for protein folding, unfolding and disaggregation

The HSP90 chaperone machinery

The yeast Hsp110 Sse1 functionally interacts with the Hsp70 chaperones SSa and Ssb

Secretion modification region-derived peptide disrupts HIV-1

Nef's interaction with mortalin and blocks virus and Nef exosome release

Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases

Heat shock protein 105 peptide vaccine could induce antitumor immune reactions in a phase I clinical trial

Gene expression profiles and protein-protein interaction network analysis in AIDS patients with HIV-associated encephalitis and dementia

Loss of expression of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer

Inhibition of heat-shock protein 90 reduces Ebola virus replication

Negative regulation of hepatitis B virus replication by cellular Hsp40/DnaJ proteins through destabilization of viral core and X proteins

Gene expression profiling of the host response to HIV-1 B, C, or A/E infection in monocyte-derived dendritic cells

Cell surface localization of the 60 kDa heat shock chaperonin protein (hsp60) in mammalian cells

A 60 kD heat-shock protein-like molecule interacts with the HIV transmembrane glycoprotein gp41

Identification of essential filovirion-associated host factors by serial proteomic analysis and RNAi screen

Evolutionary origins of Hsp90 chaperones and a deep paralogy in their bacterial ancestors

The heat shock protein 70 family of chaperones regulates all phases of the enterovirus A71 life cycle

Heat shock proteins and thermotolerance; a comparison of induction kinetics

Human immunodeficiency virus-1 Nef suppresses Hsp70-mediated Tat activation

Vif-mediated ubiquitination and degradation of APOBEC3G

Correction to: HSP60 critically regulates endogenous IL-1β production in activated microglia by stimulating NLRP3 inflammasome pathway

Hsp110 mitigates α-synuclein pathology in vivo

Defining Hsp70 subnetworks in Dengue virus replication reveals key vulnerability in flavivirus infection

Zika virus dependence on host Hsp70 provides a protective strategy against infection and disease

Heat-shock proteins as regulators of apoptosis

Interaction of the hepatitis B virus X protein (HBx) with heat shock protein 60 enhances HBx-mediated apoptosis

Siliciano RF (2020) HSF1 inhibition attenuates HIV-1 latency reversal mediated by several candidate LRAs in vitro and ex vivo

Protein synthesis in salivary glands of Drosophila melanogaster: Relation to chromosome puffs

HSPB1 is an intracellular antiviral factor against hepatitis B virus

Identification of a hTid-1 mutation which sensitizes gliomas to apoptosis

Discovery of 2-isoxazol-3-yl-acetamide analogues as heat shock protein 90 (HSP90) inhibitors with significant anti-HIV activity

A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma

Hsp40 proteins modulate humoral and cellular immune response in rheumatoid arthritis patients

Novel role of HSP40/DNAJ in the regulation of HIV-1 replication

Mitochondrial injury and cognitive function in HIV infection and methamphetamine use

Synthetic Vpr protein activates activator protein-1, c-Jun N-terminal kinase, and NF-κB and stimulates HIV-1 transcription in promonocytic cells and primary macrophages

Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target

Isolation and functional analysis of a human 70,000-dalton heat shock protein gene segment

Gyrase B inhibitor impairs HIV-1 replication by targeting Hsp90 and the capsid protein

Modulation of stress protein (hsp27 and hsp70) expression in CD4 + lymphocytic cells following acute infection with human immunodeficiency virus type-1

The J-protein family: modulating protein assembly, disassembly and translocation

Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant

Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways

DnaJ homolog Hdj2 facilitates Japanese encephalitis virus replication

Characterization of heat shock protein 110 and glucose-regulated protein 170 as cancer vaccines and the effect of fever-range hyperthermia on vaccine activity

HSP90: a promising broad-spectrum antiviral drug target

Identification of Hsc70 as an influenza virus matrix protein (M1) binding factor involved in the virus life cycle

influenza virus hemagglutinin (HA) and the viral RNA polymerase complex enhance viral pathogenicity, but only HA induces aberrant host responses in mice

Host cell factor requirement for hepatitis C virus enzyme maturation

Physical chemistry of polyglutamine: intriguing tales of a monotonous sequence

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive

Identification of prohibitin as a Chikungunya virus receptor protein

The small heat shock protein 27 is a key regulator of CD8 + CD57 + lymphocyte survival

Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy

Mitochondrial heat shock response induced by ectromelia virus is accompanied by reduced apoptotic potential in murine L929 fibroblasts

The cochaperone Cdc37 regulates the rabies virus phosphoprotein stability by targeting to Hsp90AA1 machinery

The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex

TCP1 complex is a molecular chaperone in tubulin biogenesis

Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma

Identification and characterization of the host protein DNAJC14 as a broadly active Flavivirus replication modulator

Macromolecular synthesis at the early stage of herpes simplex virus type 2 (HSV-2) latency in a human neuroblastoma cell line IMR-32: repression of late viral polypeptide synthesis and accumulation of cellular heat-shock proteins

Class 1-selective histone deacetylase (HDAC) inhibitors enhance HIV latency reversal while preserving the activity of HDAC isoforms necessary for maximal HIV gene expression

Cellular chaperonin CCT contributes to rabies virus replication during infection

Rabies viruses leader RNA interacts with host Hsc70 and inhibits virus replication

Avian chaperonin containing TCP1 subunit 5 supports influenza A virus replication by interacting with viral nucleoprotein, PB1, and PB2 proteins

Role of heat-shock protein 90 in hepatitis E virus capsid trafficking

Heat shock proteins as immunomodulants

Regulation and function of the human HSP90AA1 gene

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