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Viral interaction with molecular chaperones : role in regulating viral infection Luo, Honglin; Wong, Jerry; Xiao, Allen Jul 4, 2010

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Viral Interaction with Molecular Chaperones: Role in Regulating Viral Infection   Allen Xiao, Jerry Wong, Honglin Luo 1  The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Providence Heart + Lung Institute, St. Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada   Running title: Molecular Chaperones in Viral Infection   1 Correspondence to: Dr. Honglin Luo, The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia-St. Paul’s Hospital, 1081 Burrard St., Vancouver, British Columbia, Canada V6Z 1Y6. Phone: 1- (604) 682-2344 ext. 62847. Fax: (604) 806-9274.   E-mail: honglin.luo@hli.ubc.ca.  2 Abstract As essential effectors in protein quality control, molecular chaperones serve as the primary checkpoint to assist proper protein folding, and prevent misfolded proteins from denaturation and aggregation. In addition, chaperones can function to direct terminally-misfolded proteins to the proteolytic system for degradation. Viruses rely on host cell machineries for productive infection. Like for many other processes, various viruses have been shown to evolve mechanisms to utilize or subvert the host protein quality control machinery to support the completion of their life cycle. Furthermore, recent studies suggest that some viruses encode for their own chaperone-like proteins to enhance their infectivity. This review summarizes the current understanding of the interplay between molecular chaperones and viral proteins, highlights the chaperone activities of a number of viral proteins, and discusses potential anti-viral therapeutic strategies targeting the virus-chaperone interactions. (Words: 135)  Key Words: Chaperone, heat-shock protein, virus infection, protein folding, protein assembly   3 Introduction Molecular chaperones have traditionally been defined as a class of proteins that assist the non-covalent folding and assembly of other macromolecular structures, but are not part of these structures upon maturation. It is now evident that chaperone function is not limited to protein folding and assembly, but also include helping to prevent newly synthesized polypeptide chains and assembled subunits from aggregating into non-functional structures, transporting protein across membranes, and escorting terminally-misfolded proteins to the proteolytic system for degradation 55, 78. The general function of the intracellular molecular chaperones has been suggested mainly to involve housekeeping and cytoprotection against various environmental stresses. Studies indicate that many chapenones are induced during viral infection to either facilitate viral pathogenesis or to participate in a cellular response mechanism to alleviate the stress caused by infection 46, 60, 78. In addition to using host chaperone proteins, some viruses encode for their own chaperone-like proteins to enhance their infectivity 41, 75, 83. This review will outline the diversity and complexity of interactions between virus and chaperones, discuss the chaperone activities of a number of virus proteins, and summarize potential anti-viral therapeutic strategies targeting the virus-chaperone interactions.  Molecular Chaperones and Their Biological Functions Molecular chaperones are a family of structurally unrelated proteins which participate in the regulation of multiple biological processes to maintain cellular homeostasis. As alluded to above, chaperones bind to misfolded or unfolded polypeptides to assist in their correct folding and assembly, regulate protein transport and translocation, and facilitate misfolded polypeptides for degradation by the ubiquitin-proteasome system (Figure 1) 3, 53, 55. Dysregulation or  4 mutations in molecular chaperones has been associated with a number of human diseases, including cardiovascular diseases, neurodegenerative diseases, and cancer 58, 61. There are at least 20 different families of proteins with chaperone activity (refer to review 28  for a detailed list). The best-characterized stress-induced chaperone families are the heat shock proteins (Hsps). Hsps are classified into at least six families on the basis of their molecular weight (e.g small Hsps, Hsp40 (DnaJ), Hsp60 (chaperonins), Hsp70, Hsp90, and Hsp100) 39, 58. These families of chaperones are highly conserved during evolution and are present in both cytosol and endoplasmic reticulum (ER) in almost all cell types. They recognize and interact with various non-native polypeptides via different mechanisms of action and promote their refolding to the native state 39, 58. This process is usually regulated by one or several co- chaperones which function to modulate the activity of the chaperone. Most Hsps are constitutively synthesized but further induced in response to adverse environmental conditions such as high temperature, oxidative stress, and inflammation 39, 58. The ER contains a large set of particular molecular chaperones helping the folding and assembly of newly synthesized proteins or misfolded proteins under ER stress. Malfunction of ER chaperones induced by ER stress leads to the unfolded protein response 53, 61. There are two major groups of ER chaperones: the glucose-regulated proteins (GRPs), and the calnexin/calreticulin chaperones 53, 61. The GRP78 (also known as BiP) and GRP94 are the ER homologues of Hsp70 and Hsp90, respectively. GRP78 assists in protein folding through specifically interacting with proteins containing hydrophobic residues in their misfolded/unfolded regions. While the function of GRP94 in ER protein quality control has not been fully elucidated, it was suggested that GRP94 may provide a platform for the assembly of the large ER chaperone complex under conditions of ER stress 53, 61. Calnexin is a type I ER  5 membrane protein and calreticulin is a soluble ER lumen protein. These lectin-like ER chaperones recognize and interact with proteins that carry N-linked glycans for subsequent protein folding and assembly 53, 61. In addition to their intracellular localization and functions as discussed above, some molecular chaperones can also be present on the cell surface and/or secreted into the extracellular space under certain stress conditions. These membrane-associated or released chaperones have been reported to possess extracellular functions as important mediators of cell-cell signaling 14. Among their multiple extracellular functions, their ability in eliciting both innate and adaptive immune responses makes them attractive targets for the development of vaccine 8, 69. Document Interplay between Viruses and Host Chaperones Virus infection often leads to increased production of cellular chaperones but it remains unclear whether this is a direct effect of virus infection or an indirect response to cellular stress induced by infection 46, 60, 78. Viruses can regulate host chaperones at different levels, including transcription, translation, posttranslational modification, and cellular localization. Increased expression of heat shock proteins has been suggested to be biomarkers for some viral infections. As an example, Zhu et al. 90 found that the elevated expression of the heat shock protein GRP94 significantly correlates with the disease progression of hepatitis B virus (HBV) infection and can therefore be used as a prognostic or diagnostic biomarker for HBV-induced diseases. Similarly, the expression of GRP78/BiP and Hsp90 was also reported to be upregulated in HBV-related hepatocellular carcinomas, suggesting that these chaperones may serve as important prognostic biomarkers for HBV-induced hepatic cancer 49. Accumulating evidence has indicated that chaperones have a wide array of functions during viral infection, and that each chaperone may play different roles during a particular viral  6 infection. This review focuses on the functions of chaperones in viral host entry, viral genome nuclear import, viral replication, viral protein folding, virion assembly, host immunity regulation, and manipulating host apoptotic pathway. A summary of the interaction between viruses and host chaperones in regulating virus infection is illustrated in Figure 2.  Cell Entry and Nuclear Import Viruses are known to exploit chaperones for effective cellular entry by using them as part of the viral uncoating mechanism or as viral receptors. As an example, rotavirus entry requires the interaction with heat shock cognate protein 70 (Hsc70) at a postattachment step, functioning as part of a complex that brings about a conformational change of the viral capsid to facilitate its entry into the cytoplasm 32, 68, 89. Similarly, simian virus 40 (SV40) was reported to utilize the host protein folding machinery for virus uncoating and entry into the host cells 74. Additionally, chaperone proteins presented on cell surface can be utilized as viral receptors, such as Hsp90 and Hsp70 for dengue virus 73, Hsp70 for Japanese encephalitis virus  25, and GRP78 for coxsackievirus A9 84. After successful host internalization, most DNA viruses and some RNA viruses, such as the retroviruses and the influenza viruses, require their genome to be imported into the nucleus, where replication takes place. Rainey-Barger et al. 71 demonstrated that the ER chaperone protein ERp29 alters the conformation of polyomavirus capsid protein VP1 and exposes the internal viral protein VP2, which then perforates the ER membrane to allow the viral genome to reach the nucleus for replication. In addition, Hsc70 was also implicated to play a role in polyomavirus genome nuclear import through its association with viral capsid proteins 23.  7 During human immunodeficiency virus type 1 (HIV-1) infection, Hsp70 plays a similar role to that of the HIV-1 viral protein R (Vpr), stimulating an interaction between the viral preintegration complex and karyopherin-α to promote viral nuclear import 1. Interestingly, Iordanskiy et al. 35 argued for an antiviral role of Hsp70, where it only functions similarly as Vpr when expressed alone, but in the presence of Vpr, it neutralizes Vpr function and inhibits its nuclear translocation, rendering it unable to assist the nuclear translocation of the viral preintegration complex.  Viral Replication and Gene Expression The next steps following viral entry are the replication of the viral genome and the expression of viral proteins, which are also facilitated by host chaperons. Cyclophilins are molecular chaperones that promote protein folding through their isomerase activity 2. It was reported that hepatitis C virus (HCV) non-structural protein 5B (NS5B), an RNA-dependent RNA polymerase essential for viral genome replication, associates with the enzymatic pocket of cyclophilin A, exploiting its isomerase or chaperone activity to enhance its maturation 17. Similarly, Waxman et al. 86 also identified Hsp90 chaperone as an essential factor for the maturation and activity of the HCV NS2/3 protease, which is necessary for viral replication. Other studies further elucidated the role of Hsp90 in HCV RNA replication by forming a chaperone complex with NS5A, a component of viral replicase, and FKBP8, a member of the FK506-binding protein family 62. Hsp90 has been demonstrated to be involved in the reverse transcription of HBV genome. It was suggested that Hsp90 helps bridge the two separate reverse transcriptase domains of HBV together to enable the formation of a ribonucleoprotein complex with the HBV RNA 34. As for  8 the replication of HBV RNA genome, the glucose-regulated chaperone protein GRP94 is found to be a critical regulator in the stabilization and activation of HBV RNA polymerase, allowing its preferential binding to the HBV ε RNA 38. Furthermore, the molecular chaperonin Hsp60 is shown to participate in the activation of HBV polymerase prior to its encapsidation into the core particle, which is required for initiating HBV replication in newly infected cells 65, 66, 76. During influenza virus infection, Hsp90 interacts with the viral RNA-dependent RNA polymerase, playing a role in the assembly and nuclear transport of viral RNA polymerase subunits en route to the formation of a mature polymerase complex 57, 59. Additionally, heat shock proteins Hsp70 and Hsp40 enhance binding of the papillomavirus replication initiator E1 helicase to the origin of DNA replication, thus indirectly enhancing viral replication 50. As another example, flock house virus infection induces the expression of Hsp90, which participates in viral RNA replication as part of cellular pathways used by the virus for assembling RNA replication complexes on intracellular membranes 37. Chaperones can also be involved in regulating viral gene expression. For instance, it has been shown that HIV-1 protein Nef indirectly facilitates viral gene expression by inducing the expression of Hsp40 and interacting with Hsp40 to promote its nuclear translocation and association with the cyclin-dependent kinase 9 transcription complex that regulates long terminal repeat-mediated gene expression 42.  Folding/Assembly of Viral Protein True to their definition, a major function of chaperones is to assist the folding and assembly of viral proteins and virions into functional conformations. In particular, the  9 dependence of viruses on the ER for folding/assembly renders ER chaperones the major facilitators of proper viral morphogenesis, but other chaperones are often recruited as well. An important step in viral morphogenesis of enveloped viruses is the formation of the viral envelope. In the case of HCV infection, the ER chaperone calnexin is involved in the productive assembly of the envelope glycoproteins E1 and E2 into a heterodimer, and that it is during this dimerization process that the proper folding of the glycoproteins is achieved 20, 26, 27. Other ER chaperones, GRP78/BiP and calreticulin, were reported to interact with misfolded aggregates containing HCV viral glycoproteins, likely involved in their repair 27. HBV infection leads to the large L envelope protein acquiring a dual membrane topology in order to mediate hepatocyte receptor binding and envelopment of cytosolic nucleocapsids 70. The preS domain of L protein initially remains in the cytosol as the S domain is cotranslationally inserted into the ER membrane, and subsequently, the preS domain is translocated to the lumenal space 70. Studies revealed that Hsc70 and Hsp40 associate with L protein, likely to assist the initial suppression of the cotranslational translocation of the preS domain, and also identified the ER chaperone GRP78/BiP to be responsible for assisting the subsequent posttranslational translocation of the preS domain 4, 19, 43, 52. HBV M protein also requires the chaperone activity of calnexin, which selectively binds to the N-glycan specific to viral M protein to facilitate proper folding and trafficking 70. During polyomavirus infection, it was demonstrated that Hsc70 binds coat protein VP1 and regulates the quality and location of viral capsid assembly 21. Final assembly of viruses such as rotavirus and cytomegalovirus, occurs in the ER. It has been demonstrated that the ER chaperones GRP78/BiP, calnexin, and calreticulin are involved in the maturation of the oligosaccharide chains of the non-structural viral protein NSP4, oxidative folding of VP7, and  10 formation of disulfide bonds of VP7. All of these processes are important for correct assembly of viral particles 54. A recent study by Buchkovich et al. 11 found that protein levels of the ER chaperone GRP78/BiP are tightly regulated during cytomegalovirus infection, and showed that this regulation enhances cytoplasmic virion assembly and egress.   The well-characterized ability to facilitate glycoprotein folding renders ER chaperones essential to some viruses. For influenza virus, early maturation steps of its glycoprotein hemagglutinin involve glycosylation by N-linked glycans, leading to the binding of ER chaperones calnexin and calreticulin that facilitate productive folding of this viral glycoprotein 24. During measles virus infection, it was revealed that nascent viral fusion glycoprotein binds to calnexin as a vital step in achieving its functional conformation, and that ER chaperones may withhold the migration of viral glycoproteins to the cell surface, possibly to repair misfolding 9. Immunoprecipitation studies also showed that GRP78/BiP binds maximally to early folding intermediates of vesicular stomatitis virus glycoprotein, whereas calnexin binds subsequently to more folded molecules 33. This binding sequence is necessary for efficient folding of vesicular stomatitis virus glycoprotein and for the retention of its partially folded forms 33. Similarly, the unfolded glycoprotein of rabies virus is associated first with GRP78/BiP and subsequently with calnexin, perhaps as part of a folding mechanism 29. Other chaperone involvement in virus folding/assembly has also been described. It was shown that Hsp90 binds in a p53-independent and ATP-dependent manner to immature conformations of the SV40 large tumour antigen (TAg), possibly to assist its formation into a functional structure 56. Recently, Hsp90 was also suggested to be involved in the process of viral capsid protein folding and assembly of various picornavirus, including poliovirus, rhinovirus, and coxsackievirus 30. A virion morphology study revealed that the chaperone cyclophilin A  11 modulates HIV-1 infectivity through its interactions with viral gag structural proteins 77. In the presence of cyclosporine A, a cyclophilin A inhibitor, viral particles display immature virion morphology, indicating that cyclophilin A plays an important role in the maturation of HIV-1 particles that is essential for virion assembly 77.  Apoptosis Regulation and Host Immunity Various viruses have evolved different mechanisms to modulate the apoptotic pathway to benefit their growth in host cells. Chaperones can be utilized by viruses to participate in regulating cell apoptosis. It was demonstrated that HIV-1 infection induces overexpression of Hsp70, which interacts with Hsp27 and Vpr to protect cells from virus-induced G2 arrest and apoptosis 12, 35. As another example, the Epstein-Barr virus nuclear oncoprotein EBNA3A induces transcriptional upregulation and nuclear translocation of Hsp70 and formation of an active Hsp70 chaperone complex, which helps ensure protein stability and contributes to the immortalization of B cells as part of an anti-apoptotic effect 88. In addition, the E2 envelope protein of HCV has been shown to block virus-induced apoptosis by inducing the overexpression of the glucose-regulated chaperone proteins GRP94 44, 48. Chaperones have also been reported to facilitate apoptosis. Tanaka et al. 81 reported that during HBV infection, HBx interaction with chaperone Hsp60 brings about their colocalization in the mitochondria, where Hsp60 promotes HBx-induced apoptosis. As discussed previously, some extracellular chaperones also have immunological properties 8, 69 . They activate dendritic cells and natural killer cells, promote antigen presentation, and stimulate adaptive T-lymphocyte and humoral immune responses against antigenic peptides. During virus infection, molecular chaperones are also involved in the regulation of virus-induced  12 host immune response. For example, during Epstein-Barr virus infection, Hsp90 was identified to play an important role in promoting γδ T proliferation in B cells as part of the host immune response against virus infection 40.  The Chaperone-Like Activities of Virus Proteins In addition to utilizing host chaperones, some viral proteins also exhibit chaperone-like activity that facilitates their infection. The virus-encoded proteins with chaperone function are summarized and shown in Table 1. A well-studied viral-encoded chaperone is the SV40 TAg. This multifunctional protein has functional J domains of Hsp40, which is required for the recruitment of host Hsp70 to complete the SV40 virion assembly 75. The chaperone-like functions of TAg is also found to facilitate viral replication, transcriptional regulation, and cell cycle alteration 79. In addition, the R1 subunit of HSV ribonucleotide reductase, which protects cells against apoptosis, has chaperone-like activity similar to Hsp27 15. This chaperone activity has been proposed to have an anti-apoptotic effect that contributes to the successful infection of the virus 15 . HSV type 2 was also reported to encode for a homologue (ICP10PK) to small Hsp11 to modulate virus-induced apoptosis via activation of the ERK signaling pathway, stabilization of Bcl-2 and upregulation of other apoptosis regulators such as Hsp70 and Hsp27 31. The rotavirus non-structural glycoprotein NSP4 was also shown to act as an ER chaperone to regulate the folding of structural protein VP4 and also facilitate the transport systems through the ER membrane during virion assembly 80. During African swine fever virus infection, virus-encoded capsid-associated protein 80 functions as a chaperone assisting proper folding of the major capsid protein p73 22.  13 Virus can also encode for their own nucleic acid chaperones to assist proper viral RNA/DNA folding for efficient viral replication. The most extensively studied example is the ability of HIV-1 to encode for nucleocapsid (NC) protein to chaperone viral DNA replication 82. Specifically, the HIV-1 NC is involved in the two obligatory strand transfers required during reverse transcription to convert its genomic RNA into proviral DNA 72, 82. Furthermore, HIV-1 encoded small nuclear transcriptional activator Tat has also been demonstrated to have nucleic acid-chaperoning activities. The Tat protein is required for HIV-1 replication due to its regulation of proviral DNA transcription to generate full-length viral mRNA 41. In this paper, we have discussed only a few examples of nucleic acid chaperones in viral replication as this topic has been extensively reviewed 91.  Molecular Chaperones in Antiviral Therapy In light of the wide array of interactions between viruses and chaperones, putative therapeutic strategies against viral infection involving chaperones have emerged. Chaperone inhibitors have been explored in the development of antiviral strategies. For examples, Hsp90 inhibitors have been suggested as therapeutic agents for picornavirus infection 30. One of the best-known chaperone inhibitor is geldanamycin (GA), which specifically competes for ATP binding with Hsp90 to block its ATPase activity and thus prevent client protein cycling and maturation 60. It was shown that pharmacological inhibition of Hsp90 by GA impairs the replication of poliovirus, rhinovirus, and coxsackievirus in cells, and in vivo administration of GA significantly decreases virus load in poliovirus-infected mice without the emergence of drug- resistant escape mutants 30.  The mechanism of action of GA on picornaviral infection is likely the inhibition of viral capsid protein folding and assembly 30. Studies also showed that GA, or its  14 derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG), delays the growth of influenza virus by inhibiting nuclear import and assembly of viral RNA polymerase complex 16, and suppresses the replication of HCV through destabilizing non-structural protein NS3 85. In addition, GA inhibits HSV-1 replication by promoting aberrant folding, mislocalization, and proteasomal degradation of the viral polymerase 13, 47. In the case of HBV infection, a study by Liu et al. 51 established the multichaperone machine formed by Hsp90 and Hsp70/Hsp60 as a potential target for development of antiviral therapeutic strategies. Some host signaling molecules including phosphatidylinositol 3-kinase (PI3K) and AKT proteins are also identified to be the client proteins of the Hsp90. As for Epstein-Barr virus, a therapeutic strategy was proposed to target the PI3K/Akt pathway 36. It was speculated that Hsp90 inhibitors can disrupt the PI3K/Akt pathway, and can potentially be used for achieving control of the natural killer/T- cell lymphoma associated with Epstein-Barr virus infection 36. GA was also reported to block cytomegalovirus replication via disruption of the PI3K/Akt signaling pathway 7. Thus, the dependence of viral infection on Hsp90-dependent client proteins makes GA and other Hsp90 inhibitors promising anti-viral compounds. Other chaperone inhibitors also have therapeutic potential. Chen et al. 18 identified novel non-peptidic inhibitors against chaperone cyclophilin A as potential anti-HIV compounds. Cyclophilin inhibitors such as cyclosporine A, Debio 025, NIM811 and SCY-635 are also potential anti-HCV compounds due to their ability to inhibit HCV replication 17. Recently, Wright et al. 87 also identified the small molecular compound MAL2-11B as a novel inhibitor for the chaperone activity of the SV40 TAg, thus indicating a novel approach to combating polyomavirus-mediated disease.  15 As alluded to earlier, the ability of heat shock proteins to interact with viral proteins, together with their inherent adjuvant and immunogenic properties, render them as attractive candidates for the development of anti-viral vaccines 10. Lehner et al. 45 suggested a novel strategy of immunization with Hsp70 linked to antigen to generate both cognate and innate immunity to prevent binding and transmission of simian immunodeficiency virus. In particular, Babaahmady et al. 5 showed that microbial Hsp70 exerts a dose-dependent inhibitory effect on HIV-1 infection of CD4+ T cells, and proposed a combined treatment with Hsp70 and antibody to the CCR5 strain of CD4+ T cells as a potential immunization strategy against HIV-1 infection. They also proposed a vaccination approach of utilizing a Hsp70-containing trimolecular complex of human antisera to elicit broadly neutralizing antibody activity to HIV-1 6. Similarly, Peng et al. 67  identified the mycobacterium tuberculosis Hsp70 as a potential adjuvant for the development of prophylactic and therapeutic vaccines for chronic HBV infection. Hsp70 was also proposed to be useful in the design of vaccines for HSV 63, 64. Table 2 summarizes the therapeutic strategies targeting molecular chaperones for the treatment of virus infection.  Conclusion  It is evident that chaperones are elicited during a wide array of viral infections to play important roles at various stages of the viral life cycle to either enhance or inhibit pathogenesis. This review of the roles played by heat shock proteins and other chaperones is by no means comprehensive, but simply a broad sketch of studies done in this expanding area. 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Zarate S, Cuadras MA, Espinosa R, Romero P, Juarez KO, Camacho-Nuez M, Arias CF, Lopez S (2003) Interaction of rotaviruses with Hsc70 during cell entry is mediated by VP5. J Virol 77: 7254-7260 90. Zhu XD, Li CL, Lang ZW, Gao GF, Tien P (2004) Significant correlation between expression level of HSP gp96 and progression of hepatitis B virus induced diseases. World J Gastroenterol 10: 1141-1145 91. Zuniga S, Sola I, Cruz JL, Enjuanes L (2009) Role of RNA chaperones in virus replication. Virus Res 139: 253-266   24 Table 1. Virus-encoded chaperones which assist viral infection   SV40, simian virus 40; TAg, large tumor antigen; NSP4, non-structural protein 4; Tat, transcriptional activator; Hsp, heat shock protein; Hsc, heat shock cognate protein; VP4, viral protein 4; HSV, herpes simplex virus; HIV, human immunodeficiency virus ; ICP10PK, herpes simplex virus type 2 anti-apoptotic protein. Virus Viral protein with chaperone-like activity Function Effect on viral infection Reference SV40 TAg Has J Domain of Hsp40 required for host Hsp70 recruitment Viral assembly   Spence et al. 1994 [75]   Interaction with host Hsc70 Viral replication Sullivan and Pipas 2002 [79]  HSV Ribonucleotide reductase S1 subunit  Hsp27-like chaperone activity  Anti-apoptosis  Chabaud et al. 2003  [15]   ICP10PK  Homologue to host Hsp11  Modulation of virus- induced apoptosis  Gober et al. 2005 [31]  NSP4  ER chaperone-like activity Structural protein VP4 folding  Suzuki 1996 [80]  African swine fever virus  Capsid-associated protein 80 Chaperone-like activity Capsid protein p73 folding Cobblod et al. 2001 [22] HIV Tat  Nucleic acid chaperone Viral DNA replication Kuciak et al. 2008  [41] Nucleocapsid protein Nucleic acid chaperone Viral DNA replication Thomas et al. 2008 [82]; Ramalanjaona et al. 2007 [72]   25 Table 2. Therapeutic potentials by targeting molecular chaperones for the treatment of viral infection  Virus Treatment Chaperone Mechanism of action Reference Poliovirus, Rhinovirus, Coxsackievirus  Geldanamycin (Hsp90 inhibitor) Hsp90 Disrupt viral capsid protein folding/assembly Geller et al. 2007 [30]  Influenza virus Gelanamycin or its derivative 17-AAG (Hsp90 inhibitors) Hsp90  Prevent nuclear import and assembly of viral RNA polymerase complex  Chase et al. 2008  [16]  HCV  17-AAG (Hsp90 inhibitor)  Hsp90  Destabilize HCV non- structural protein NS3 Ujino et al. 2009 [85] Cyclosporine A, Debio 025, NIM811, and SCY- 635 (Cyclophilin A inhibitors)  Cyclophilin A Inhibit the chaperone activity of cyclophilin A Chatterji et al. 2009 [17]  HSV-1 Geldanamycin (Hsp90 inhibitor)   Hsp90    Promote aberrant folding, mislocalization, and degradation of viral polymerase  Burch et  al. 2005 [13]; Li et al. 2004 [47]  Hsp70 vaccine Hsp70 Stimulate host innate and adaptive immune responses  Pack et al. 2005 [63]; Pack et al. 2008 [64] HBV 17-AAG (Hsp90 inhibitor)  Hsp90/Hsp70/ Hsp60 Disrupt the interaction of Hsp90 with Hsp70/Hsp60 Liu et al. 2009 [51]  Hsp70 vaccine Hsp70 Elicit host immune responses  Peng et al. 2006 [67] Cytomegalovirus Geldanamycin (Hsp90 inhibitor) Hsp90 Disrupt PI3K/Akt pathway  Basha et al. 2005 [7] Epstein-Barr virus Gelanamycin or its derivative 17-AAG (Hsp90 inhibitors)  Hsp90 Disrupt PI3K/Akt pathway Jeon et al. 2007 [36] HIV Small molecular compounds Cyclophilin A  Inhibit the chaperone activity of cyclophilin A Chen et al. 2007 [18]  Hsp70 vaccine Hsp70 Elicit host immunity against HIV  Babaahmady et al. 2007 [5]; Babaahmady et al. 2008 [6] SV40 Small molecular compound TAg Inhibit TAg’s chaperone activity  Wright et al. 2009  [87]  SIV Hsp70 vaccine Hsp70 Elicit host innate and adaptive immunity  Lehner et al. 2000 [45]   26  17-AAG, 17-allylamino-17-demethoxygeldanamycin ; Hsp, heat shock protein; HCV, hepatitis C virus ; NS3, non-structural protein 3 ; HBV, hepatitis B virus ; PI3K, phosphatidylinositol 3- kinase; HSV, herpes simplex virus; HIV, human immunodeficiency virus ; SV40, simian virus 40 ; TAg, large tumor antigen ; SIV, simian immunodeficiency virus.    27 Figure legends  Figure 1. Schematic illustration of the functions of molecular chaperones. Molecular chaperones assist folding and assembly of newly synthesized polypeptides to the native proteins. Chaperones also bind to misfolded proteins induced by stress to help correct folding and assembly. Terminally-misfolded or unfolded proteins are escorted by chaperones for degradation through the ubiquitin-proteasome system.  Figure 2. Interplay between viruses and host chaperones. Virus infection can lead to increased production of host chaperones either as a direct effect of virus infection or an indirect response to cellular stress induced by infection. Through different mechanisms, both direct and indirect, chaperones can have diverse pro-viral or anti-viral roles during various stages of the viral life cycle including cell entry, nuclear import, viral genome replication, and the folding/assembly of viral proteins. In addition, chaperones can have a significant effect on viral pathogenesis due to their involvement in the regulation of host immunity and apoptosis. Hsc70, heat shock cognate protein 70; Hsp: heat shock protein; GRP, glucose-regulated protein; HCV, hepatitis C virus; HBV, hepatitis B virus; HIV, human immunodeficiency virus.           28     Figure 1.  Proteasome Misfolded Native Aggregates NUCLEUS Endoplasmic Reticulum Degradation Nascent Stress Polyubiquitination ubiquitin chaperone chaperone chaperone chaperone chaperone chaperone chaperone  29 Figure 2.                                            Cell Entry Rotavirus Dengue Virus HIV-1 Hsc70 Viral Replication HCV Cyclophilin A HBV Influenza Virus Host Immunity/Apoptosis Hsp70 Nuclear Import Folding/Assembly HIV-1 Epstein- Barr virus HCV GRP94 HBV NUCLEUS ER HCV Calreticulin Rotavirus Calnexin Calreticulin Hsp90 Calnexin Polyomavirus Hsp70 Hsp60 Hsp70 Hsc70 GRP94 Hsp90 Hsp90 Hsp90 HBV Polyomavirus Hsc70 GRP78/BiP Calreticulin Calnexin Hsc70 Hsp40 Hsp70 GRP78/BiP Virus


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