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Published in final edited form as: Rev Infect. 2010 July 1; 1(3): 151–157.
Regulation of host innate immunity by hepatitis C virus: crosstalk between hepatocyte and NK/DC Sung-Jae Park1,2 and Young S. Hahn1,3,4,* 1Beirne B Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA 2Department
of Internal Medicine, College of Medicine, Inje University, Busan, Korea
3Department
of Microbiology, University of Virginia, Charlottesville, VA 22908, USA
4Department
of Pathology, University of Virginia, Charlottesville, VA 22908, USA
Abstract NIH-PA Author Manuscript
Hepatitis C virus (HCV) infection in humans is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma. CD8+ T cells are involved in controlling HCV infection; but, in chronic HCV patients, severe CD4+ and CD8+ T cell dysfunction has been observed. This suggests that HCV may employ numerous mechanisms to counteract or possibly suppress the host T cell responses. The primary site of HCV replication occurs within hepatocytes in the liver. As a result of liver enodothelial cells perforated by fenestrations, parenchymal cells (hepatocytes) are not separated by a basal membrane, and thereby HCV-infected hepatocytes are extensively capable of interacting with innate immune cells including NK, DC. Recent studies reveal that the function of NK and DC function is significantly impaired in chronic HCV patients. Given a critical role of NK and DC in limiting HCV replication at the early phase of viral infection, it is likely that HCV-infected hepatocytes might be responsible for impairing NK and DC function by enhancing the expression of immunoregulatory molecules (either soluble or cell surface). Thus, this impairment of innate immunity attributes to the failure of generating effective T cell responses to clear HCV infection. In this article, we will review studies highlighting the regulation of innate immunity by HCV and crosstalk between hepatocytes and NK/DC in the hepatic environment.
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Keywords innate immunity; TLR activation; evasion of TLR signaling; the impaired function of NK; DC
Introduction Hepatitis C virus (HCV) infection is a growing public health problem and over 130 million people are chronically infected worldwide [1]. Unlike hepatitis B virus (HBV), HCV evades effective immune responses and establishes chronic infection in more than 80% of infected individuals. Persistent HCV infection predisposes to the increased incidence of complications such as liver cirrhosis and hepatocellular carcinoma [2]. Unfortunately a protective vaccine is not available and therapeutic options for HCV patients are still limited. Current standard therapy with pegylated interferon combined with ribavirin is often not tolerable because of side effects, and approximately half of individuals receiving anti-HCV
*
Corresponding author: [email protected].
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therapy mount a sustained virologic response (SVR). It is also worth-while to point out that, in spite of type I interferon (IFN) produced during acute infection, HCV replication is sustained and HCV infection fails to be cleared and establishes persistent infection. This suggests that HCV evolves multiple strategies to attenuate IFN-mediated antiviral mechanisms and counteract with host immune responses. An understanding of the mechanisms involved in HCV-mediated immune evasion strategies is a critical step to help the design of novel antiviral therapy and the development of vaccine. Hepatocytes are the primary target of HCV infection and replication. Hepatocytes comprise 70–80% of all liver cells and lie underneath the liver sinusoids collecting the blood from artery and intestine. Unlike most blood vessels, liver enodothelial cells do not form tight junctions and are perforated by fenestrations. Therefore, parenchymal cells are not separated by a basal membrane and there are extensive interactions of HCV-infected hepatocytes with immune cells, including NK and DC, as shown in Figure 1. Although early studies suggest that hepatocytes express low levels of class I MHC molecules, hepatocytes are emerging as an important player in regulating intrahepatic immune responses. In this review, we will provide a brief discussion of the HCV life cycle and describe the potential immunoregulatory mechanisms involving several cell types such as hepatocytes, NK, and DC from an immunological point of view.
The HCV life cycle NIH-PA Author Manuscript NIH-PA Author Manuscript
HCV is an enveloped positive stranded RNA virus belonging to the Flaviviridae family. The precise process by which HCV enters hepatocytes is not yet fully understood, but the entry of HCV may require lipoproteins and other cellular proteins [3]. Low density lipoprotein (LDL) receptor appears to be involved in endocytosis of HCV as antibodies to LDL receptor prevented HCV entry in a dose dependent manner and endocytosis of HCV is also competitively inhibited by LDL and very low density lipoprotein (VLDL), but not by high density lipoprotein (HDL) [4, 5]. In addition, HCV entry into hepatocytes is associated with other cellular proteins: the tetraspanin CD81, the scavenger receptor class B type I (SR-BI), and the tight junction proteins claudin-1, -6 or −9 [6–9]. While HCV entry appears to be reduced in the presence of antibodies to CD81, or the downregulation of CD81 in hepatoma cells [10], SR-BI is thought to be an additional factor to mediate the entry of HCV into cells [7, 11]. However, coexpression of CD81 and SR-BI are not sufficient for HCV entry, suggesting that other proteins are involved in HCV entry [6, 12]. Indeed, recent studies report that additional cellular factors such as the tight junction proteins, claudin 1 (CLDN1) and occludin are involved in the HCV entry [6, 13]. Nevertheless, certain cell types are still non-permissive despite the expression of CD81, SR-BI and CLDN1 and this indicates that additional unknown factor(s) may be necessary for the entry of HCV into hepatocytes [14]. Since several proteins have been identified as crucial factors for HCV entry, HCV entry occurs by the sequential steps of numerous cell surface molecules displayed in hepatocytes. After endocytosis, the positive strand HCV genome undergoes an uncoating process and is exposed to host cell machinery. The 5’ non-translated region of the HCV genome contains an internal ribosome entry site (IRESs). The viral genome is then translated as a polyprotein in the cytoplasm, and the HCV replication appears to occur in association with the endoplasmic reticulum. The individual structural (core, E1, E2) and non-structural proteins (NS2, NS3, NS4A, B, NS5A, B) are proteolytically processed from the poly-protein. To counteract with host immunity against HCV, viral proteins such as core, NS3A, NS5A, have been shown to inhibit the production of type I IFN as described below and play a role in the establishment of HCV persistent infection. Given the immunoregulatory role of type I IFN in activating innate immunity, particularly NK cell activation, the inhibition of the type I IFN response by HCV might directly be involved in the impaired innate and adaptive immunity as observed in chronic HCV patients.
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RIG-I/TLR activation and interference of RIG-I/TLR signaling by HCV NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Pathogen recognition receptors (PRRs) recognize constituents from microbial pathogens and trigger anti-viral responses by promoting the production of inflammatory cytokines. While HCV is able to activate toll like receptor3 (TLR3) and retinoic acid inducible gene I (RIG-I) pathway, several viral factors have been reported to inhibit the innate immune response and favors for virus survival [15, 16]. During HCV infection in hepatocytes, two PRRs (RIG-I, TLR3) recognize HCV RNA and trigger signaling cascades that lead to the synthesis of multiple cytokines, including type I IFNs and the activation of host defense mechanism (Figure 2A). RIG-I senses the poly-uridine motif of the HCV genome 3’ non-translated region in the cytoplasm recruits the adapter molecule INF-β promoter stimulator protein 1 (IPS-1) localized to the membrane of mitochondria [17, 18]. On the other hand, TLR3 senses double-stranded RNA in the endosome and recruits the adapter molecule Toll-IL-1 receptor domain-containing adapter inducing INF-β (TRIF) [19]. TRIF is essential for double-stranded RNA-stimulated synthesis of type 1 IFNs signaling. Nevertheless, both RIG-I and TLR3 pathways initiate a signaling cascade that result in INF-β synthesis [19, 20]. Secreted INF-β then activates the JAK/STAT signaling cascade by binding to the INFα/β receptor [19]. This cascade results in the transcription of IFN-stimulating genes (ISGs) including protein kinase R (PKR), 2’,5’ oligoadenylate synthetases-RNaseL [21–24]. These products play a pivotal role in limiting virus infection by suppressing viral replication and modulating adaptive immune response [25]. As a counteractive mechanism for TLR-induced anti-viral responses, HCV develops strategies to evade these immune responses in part through its ability to antagonize signaling to the IFN response at multiple levels (Figure 2B). First, the HCV NS3/4A protease inactivates IPS-1 by cleaving and delocalizing from the mitochondria membrane, thus preventing RIG-I signaling [11, 17, 26]. Importantly, liver tissues from chronic infected HCV patients demonstrated redistribution of IPS-1, which provides strong evidence that IPS-1 is targeted and is an essential component of IFN transcription [27]. In addition, NS3/4A protease has also been demonstrated to disrupt TLR3 pathway by accelerating degradation of TRIF in vitro [28]. As a consequence of cleavage of IPS-1 and TRIF by NS3/4A, IFN synthesis is reduced in HCV-infected cells, and the host defense mechanism is likely to be impaired [11]. It suggests that the protease inhibitors, which are now in clinical trial, may not only reduce viral replication, but also restore host immunity [11]. Second, HCV core inhibits IFN signaling by interfering with JAK/STAT pathway [29] whereas HCV NS5A blocks 2’–5’ oligoadenylate synthetase (2’–5’ OAS) and induces IL-8, which inhibits overall ISG expression [19, 30]. Lastly, HCV E2 and NS5A inhibit PKR, which leads to increase the phosphorylation of eIF2α and inhibits protein synthesis in infected cells [31, 32]. The analysis of PKR activation among various HCV genotypes demonstrated that HCV genotype 1 is relatively resistant to IFN therapy and inhibits PKR more efficiently than HCV genotype 2 and 3 [32, 33]. These findings provide an explanation to why patients with genotype 2 and 3 have a greater SVR rate than those with genotype 1. As these viral escape mechanisms have been identified in cell culture systems, more data wait for demonstrating their physiological relevance during a natural HCV infection. Given a crucial role of type I IFN in the activation of NK cells, the inhibition of type I IFN synthesis by HCV proteins might be critical for impairing the function of NK and DC shown in chronic HCV patients as described below. Further studies are necessary to elucidate the potential role of HCV-induced inhibition of type I IFN synthesis in impairing NK cell activation, resulting in affecting DC activation via NK-DC crosstalk.
Inhibition of NK antiviral activity by HCV Natural Killer (NK) cells are enriched in the liver and constitute the first line of host defense mechanisms against pathogen [34]: the intrahepatic lymphocytes contain 37% NK cells
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compare to 13% NK cells present in the peripheral blood [35]. Following viral infection, NK cells can penetrate the endothelial cells, enter the space of Disse, and directly contact the microvilli of hepatocytes. NK cells activated during the early stages of viral infection play a pivotal role in guiding first defense against viral infection and linking between innate and adaptive responses. NK cell function is modulated by the expression of inhibitory receptors (Ig-like killer inhibitory receptor, CD94/NKG2 receptors) and activating receptors (NKp46, NKp30, NKp44, NKG2D). During the early stage of HCV infection, NK cells are activated by type I IFNs and DCs [36, 37] and the activated NK cells can inhibit HCV infection by killing HCV-infected hepatocytes directly, secreting cytokines such as IFN-γ that inhibit HCV replication and stimulating adaptive immune response [38–43]. Thus, NK cells play an important role in controlling acute HCV infection [43]. However, the frequency of NK cells is decreased in peripheral blood of chronic HCV infected patients [44, 45]. Interestingly, patients who cleared HCV with antiviral therapy showed similar frequency NK cells compared to healthy controls [44], and intrahepatic NK cells also correlate positively with sustained response to IFN/ribavirin treatment for chronic HCV patients [46]. Notably, in chronic HCV patients, NK cells are functionally impaired and the ability of NK cells to augment DC function is severely compromised [38, 47]. These results suggest that HCV evades NK cell surveillance via multiple mechanisms. The binding of the HCV envelope protein, HCV-E2, to CD81 (an ubiquitous cellular receptor for HCV) has been reported to block NK cell activation with inhibition of IFN-γ production, and cytotoxic granule release [48, 49]. In addition, the expression of HCV core protein at hepatocytes enhances the expression of HLA-E, a ligand of NK cell inhibitory receptor NKG2A, and inhibits NK cells function [50, 51]. Thus, it is likely that the intracellular HCV core alters the expression of NK cell receptor repertoire, favoring expansion of NK inhibitory receptors. Although most of in vitro cell culture experiments and clinical studies suggest that NK cells play a critical role in controlling HCV infection, the development of reliable in vivo models is an essential step to clarify the function of NK cells in the complex network of innate and adaptive immune responses. Importantly, recent studies reported that NK cells can crosstalk with DC, resulting in the regulation of adaptive T cell responses. Thus, it is possible that the impaired DC function as described below might be as a result of the inhibition of NK cell activation in chronic HCV patients.
Impairment of DC function by HCV
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Antigen-presenting cells, such as DC, have an important role in initiating immune responses to viral infection and also express different TLR, thus responding to diverse pathogens [52]. Importantly, DC play a crucial role in linking the innate immunity to the adaptive immunity by presenting viral antigens to T cells [53]. Impairment of DC can severely disrupt the ability of the host immune response to clear viral infection, thereby resulting in ongoing viral infection. Numerous studies have also reported that patients with chronic HCV infection have decreased numbers of peripheral myeloid and plasmacytoid DC [35, 54–56]. This could be possibly due to the migration of DC from the peripheral blood to the infected liver. This possibility is further supported by recent studies that intrahepatic accumulation of DC in chronic HCV hepatitis patients is increased markedly compared to normal control liver specimens [57]. However, the intrahepatic trapping of DC may not be specific to chronic HCV infection, as this has been shown in another liver-tropic viral infection, i.e. chronic HBV infection. Human DCs are classified into two major subsets: myeloid DCs and plasmacytoid DCs [52, 58–60]. Myeloid DCs are considered as classical APCs, as they are able to initiate the activation of naïve and effector T cells. Thus, defective myeloid DC function could result in insufficient Th1 cell development. Notably, in chronic HCV patients, the ability of myeloid DCs to stimulate allogeneic T cells is diminished [54, 61, 62]. Myeloid DCs from chronic HCV patients display increased IL-10 and decreased IL-12 production in response to stimulation such as poly(I:C) or CD40 [54, 61–64]. As one of viral Rev Infect. Author manuscript; available in PMC 2014 March 29.
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factor(s) to impair DC function, extracellular HCV core has been reported to inhibit the production of IL-12 by human myeloid DCs in response to TLR stimulation [65]. Based on the pivotal role of cytokines (i.e. type I IFN, IL-12) secreted by DC in NK activation during the early phase of viral infection, future studies are necessary for paying attention to elucidate the contribution of impaired DC function in chronic HCV patients on altering NK cell activation. Importantly, plasmacytoid DC play a pivotal role in generating anti-viral responses by secretion of high levels of IFN-α in response to TLR7 and TLR9 stimulation [66, 67]. In HCV infection, the function of plasmacytoid DCs is impaired compared to healthy control and their ability to produce IFN-α upon in vitro stimulation is reduced [54, 56, 61, 68–70]. Interestingly, patients who resolved their HCV infection spontaneously and patients who responded to therapy showed similar numbers of plasmacytoid DC and IFN-α production as the healthy control group [56, 68]. Taken together, the impaired DC function in HCV patients might explain a failure in generating effective T cell responses during HCV infection. Given that inflammatory cytokines, particularly IL-12, are crucial for activating NK cells, it is possible that the inhibition of such cytokines might be also involved in the inhibition of NK cell activation as described above.
Future Studies
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HCV utilized several mechanisms related to escape innate and adaptive immune responses at multiple steps. HCV needs these strategies including disruptions of mediators in intracellular antiviral defenses, as well as interruptions of host immune processes, for survival in the host. Although our understanding at the molecular level that HCV may evade detection and clearance by the host immune system was advanced after the cell culture system was developed, the potential mechanisms to clinical persistent infection still remain to be defined. In addition to recent advances in cell biology and immunology of the host, it is hoped that small animal models will be developed to allow evaluation of antiviral agents, vaccines, and immunotherapies. And the benefits of such advances might help patients who suffer from serious forms of liver disease with improved personal life, and it may ultimately become possible to provide protection against viral infection. Furthermore, although several aspects of immune responses are not functional during chronic HCV infection, the initial causal factor(s) responsible for impaired responses to HCV has yet to be determined. Given that NK and DC recruited to infection sites following viral infection lead to the promotion of NK-DC cross-talk, influencing CD8+ T cell responses, it is critical for a better understanding of the mechanisms of hepatic NK cell function and the cooperation between hepatic NK cells and other cells (i.e. DC, CD8+ T cells) in the liver.
Acknowledgments NIH-PA Author Manuscript
We thank the members of Hahn laboratory for helpful discussions. This work was supported by the GlaxoSmithKline Research Fund of the Korean Association for the Study of the Liver and the Inje University in 2006 to SJP, and NIH R01DK066754, U19AI063222 to YSH.
Abbreviations HCV
heptatitis C virus
NK
natural killer cells
DC
dendritic cells
References 1. Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol. 2004; 44:20–29.
Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
Page 6
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
2. Davis GL, Albright JE, Cook SF, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003; 9:331–338. 3. Burlone ME, Budkowska A. Hepatitis C virus cell entry: role of lipoproteins and cellular receptors. J Gen Virol. 2009; 90:1055–1070. 4. Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1999; 96:12766– 12771. 5. Petit JM, Minello A, Duvillard L, Jooste V, Monier S, Texier V, Bour JB, Poussier A, Gambert P, Verges B, Hillon P. Cell surface expression of LDL receptor in chronic hepatitis C: correlation with viral load. Am J Physiol Endocrinol Metab. 2007; 293:E416–E420. 6. Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B, Hatziioannou T, McKeating JA, Bieniasz PD, Rice CM. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature. 2007; 446:801–805. 7. Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G, Traboni C, Nicosia A, Cortese R, Vitelli A. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. Embo J. 2002; 21:5017–5025. 8. Zhang J, Randall G, Higginbottom A, Monk P, Rice CM, McKeating JA. CD81 is required for hepatitis C virus glycoprotein-mediated viral infection. J Virol. 2004; 78:1448–1455. 9. Zheng A, Yuan F, Li Y, Zhu F, Hou P, Li J, Song X, Ding M, Deng H. Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus. J Virol. 2007; 81:12465–12471. 10. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S. Binding of hepatitis C virus to CD81. Science. 1998; 282:938–941. 11. Sklan EH, Charuworn P, Pang PS, Glenn JS. Mechanisms of HCV survival in the host. Nat Rev Gastroenterol Hepatol. 2009; 6:217–227. 12. Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM, McKeating JA. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci U S A. 2003; 100:7271–7276. 13. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP, Rice CM. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature. 2009; 457:882–886. 14. Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol. 2007; 5:453–463. 15. Gale M Jr, Foy EM. Evasion of intracellular host defence by hepatitis C virus. Nature. 2005; 436:939–945. 16. Wohnsland A, Hofmann WP, Sarrazin C. Viral determinants of resistance to treatment in patients with hepatitis C. Clin Microbiol Rev. 2007; 20:23–38. 17. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, Gale M Jr. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci U S A. 2005; 102:2986–2991. 18. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr. Innate immunity induced by compositiondependent RIG-I recognition of hepatitis C virus RNA. Nature. 2008; 454:523–527. 19. Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009; 119:1745–1754. 20. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008; 1143:1–20. 21. Guo JT, Sohn JA, Zhu Q, Seeger C. Mechanism of the interferon alpha response against hepatitis C virus replicons. Virology. 2004; 325:71–81. 22. Hui DJ, Bhasker CR, Merrick WC, Sen GC. Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2.GTP.Met-tRNAi. J Biol Chem. 2003; 278:39477–39482. 23. Pflugheber J, Fredericksen B, Sumpter R Jr, Wang C, Ware F, Sodora DL, Gale M Jr. Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc Natl Acad Sci U S A. 2002; 99:4650–4655.
Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
Page 7
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
24. Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM. New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. J Virol. 2005; 79:6291–6298. 25. Sen GC. Viruses and interferons. Annu Rev Microbiol. 2001; 55:255–281. 26. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A. 2005; 102:17717–17722. 27. Loo YM, Owen DM, Li K, Erickson AK, Johnson CL, Fish PM, Carney DS, Wang T, Ishida H, Yoneyama M, Fujita T, Saito T, Lee WM, Hagedorn CH, Lau DT, Weinman SA, Lemon SM, Gale M Jr. Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci U S A. 2006; 103:6001–6006. 28. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, Ikeda M, Ray SC, Gale M Jr, Lemon SM. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A. 2005; 102:2992–2997. 29. Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Haussinger D. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. Faseb J. 2003; 17:488–490. 30. Polyak SJ, Khabar KS, Paschal DM, Ezelle HJ, Duverlie G, Barber GN, Levy DE, Mukaida N, Gretch DR. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol. 2001; 75:6095–6106. 31. Gale MJ Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997; 230:217–227. 32. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science. 1999; 285:107–110. 33. Noguchi T, Satoh S, Noshi T, Hatada E, Fukuda R, Kawai A, Ikeda S, Hijikata M, Shimotohno K. Effects of mutation in hepatitis C virus nonstructural protein 5A on interferon resistance mediated by inhibition of PKR kinase activity in mammalian cells. Microbiol Immunol. 2001; 45:829–840. 34. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001; 1:41–49. 35. Szabo G, Chang S, Dolganiuc A. Altered innate immunity in chronic hepatitis C infection: cause or effect? Hepatology. 2007; 46:1279–1290. 36. Ebihara T, Shingai M, Matsumoto M, Wakita T, Seya T. Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells. Hepatology. 2008; 48:48–58. 37. Shin EC, Seifert U, Kato T, Rice CM, Feinstone SM, Kloetzel PM, Rehermann B. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J Clin Invest. 2006; 116:3006–3014. 38. Ahmad A, Alvarez F. Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis. J Leukoc Biol. 2004; 76:743–759. 39. Frese M, Schwarzle V, Barth K, Krieger N, Lohmann V, Mihm S, Haller O, Bartenschlager R. Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology. 2002; 35:694–703. 40. Golden-Mason L, Rosen HR. Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transpl. 2006; 12:363–372. 41. Larkin J, Bost A, Glass JI, Tan SL. Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons. J Interferon Cytokine Res. 2006; 26:854– 865. 42. Wang SH, Huang CX, Ye L, Wang X, Song L, Wang YJ, Liang H, Huang XY, Ho WZ. Natural killer cells suppress full cycle HCV infection of human hepatocytes. J Viral Hepat. 2008; 15:855– 864. 43. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009; 86:513–528. 44. Morishima C, Paschal DM, Wang CC, Yoshihara CS, Wood BL, Yeo AE, Emerson SS, Shuhart MC, Gretch DR. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology. 2006; 43:573–580. Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
Page 8
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45. Nattermann J, Feldmann G, Ahlenstiel G, Langhans B, Sauerbruch T, Spengler U. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut. 2006; 55:869–877. 46. Yamagiwa S, Matsuda Y, Ichida T, Honda Y, Takamura M, Sugahara S, Ishikawa T, Ohkoshi S, Sato Y, Aoyagi Y. Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells. Hepatol Res. 2008; 38:664–672. 47. Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T, Kanazawa Y, Hiramatsu N, Hayashi N. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol. 2004; 173:6072–6081. 48. Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S, D'Oro U, Mosca M, Filliponi F, Brunetto RM, Bonino F, Abrignani S, Valiante NM. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med. 2002; 195:35–41. 49. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med. 2002; 195:43–49. 50. Nattermann J, Nischalke HD, Hofmeister V, Ahlenstiel G, Zimmermann H, Leifeld L, Weiss EH, Sauerbruch T, Spengler U. The HLA-A2 restricted T cell epitope HCV core 35–44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells. Am J Pathol. 2005; 166:443–453. 51. Schulte D, Vogel M, Langhans B, Kramer B, Korner C, Nischalke HD, Steinberg V, Michalk M, Berg T, Rockstroh JK, Sauerbruch T, Spengler U, Nattermann J. The HLA-E(R)/HLA-E(R) genotype affects the natural course of hepatitis C virus (HCV) infection and is associated with HLA-E-restricted recognition of an HCV-derived peptide by interferon-gamma-secreting human CD8(+) T cells. J Infect Dis. 2009; 200:1397–1401. 52. Liu B, Woltman AM, Janssen HL, Boonstra A. Modulation of dendritic cell function by persistent viruses. J Leukoc Biol. 2009; 85:205–214. 53. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol. 2002; 20:621–667. 54. Kanto T, Inoue M, Miyatake H, Sato A, Sakakibara M, Yakushijin T, Oki C, Itose I, Hiramatsu N, Takehara T, Kasahara A, Hayashi N. Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J Infect Dis. 2004; 190:1919–1926. 55. Tsubouchi E, Akbar SM, Murakami H, Horiike N, Onji M. Isolation and functional analysis of circulating dendritic cells from hepatitis C virus (HCV) RNA-positive and HCV RNA-negative patients with chronic hepatitis C: role of antiviral therapy. Clin Exp Immunol. 2004; 137:417–423. 56. Wertheimer AM, Bakke A, Rosen HR. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology. 2004; 40:335–345. 57. Nattermann J, Zimmermann H, Iwan A, von Lilienfeld-Toal M, Leifeld L, Nischalke HD, Langhans B, Sauerbruch T, Spengler U. Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C. Hepatology. 2006; 44:945–954. 58. O'Doherty U, Pen M, Gezelter S, Swiggard WJ, Betjes M, Bhardwaj N, Steinman RM. Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology. 1994; 82:487–493. 59. Robinson SP, Patterson S, English N, Davies D, Knight SC, Reid CD. Human peripheral blood contains two distinct lineages of dendritic cells. Eur J Immunol. 1999; 29:2769–2778. 60. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Liu YJ. The nature of the principal type 1 interferon-producing cells in human blood. Science. 1999; 284:1835–1837. 61. Averill L, Lee WM, Karandikar NJ. Differential dysfunction in dendritic cell subsets during chronic HCV infection. Clin Immunol. 2007; 123:40–49. 62. Kanto T, Inoue M, Miyazaki M, Itose I, Miyatake H, Sakakibara M, Yakushijin T, Kaimori A, Oki C, Hiramatsu N, Kasahara A, Hayashi N. Impaired function of dendritic cells circulating in
Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
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patients infected with hepatitis C virus who have persistently normal alanine aminotransferase levels. Intervirology. 2006; 49:58–63. 63. Della Bella S, Crosignani A, Riva A, Presicce P, Benetti A, Longhi R, Podda M, Villa ML. Decrease and dysfunction of dendritic cells correlate with impaired hepatitis C virus-specific CD4+ T-cell proliferation in patients with hepatitis C virus infection. Immunology. 2007; 121:283–292. 64. Rodrigue-Gervais IG, Jouan L, Beaule G, Sauve D, Bruneau J, Willems B, Sekaly RP, Lamarre D. Poly(I:C) and lipopolysaccharide innate sensing functions of circulating human myeloid dendritic cells are affected in vivo in hepatitis C virus-infected patients. J Virol. 2007; 81:5537–5546. 65. Waggoner SN, Hall CH, Hahn YS. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. J Leukoc Biol. 2007; 82:1407–1419. 66. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001; 194:863–869. 67. Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005; 23:275–306. 68. Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, Szabo G. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006; 177:6758–6768. 69. Shiina M, Rehermann B. Cell culture-produced hepatitis C virus impairs plasmacytoid dendritic cell function. Hepatology. 2008; 47:385–395. 70. Ulsenheimer A, Gerlach JT, Jung MC, Gruener N, Wachtler M, Backmund M, Santantonio T, Schraut W, Heeg MH, Schirren CA, Zachoval R, Pape GR, Diepolder HM. Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection. Hepatology. 2005; 41:643–651.
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Fig 1.
A diagram for the liver sinusoid. Under the normal condition, due the physical barrier formed by portal endothelial cells and basal membrane, innate immune cells, in particular, immature DC are easily not accessible to interact with hepatocytes. However, following the inflammatory stimuli including liver tropic HCV infection, NK and DC can direct contact with HCV-infected hepatocytes due to the increased permeabilization of endothelia membrane. So there are extensive interactions between HCV-infected hepatocytes and NK/ DC. These interaction might play a critical role in regulating antiviral T cell responses.
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Fig 2.
A) Pathogen recognition receptors RIG-I and TLR3 detect HCV ds RNA and activate via their adaptor molecules IPS-1 and TRIF. These signaling cascades result in transcription of INF-β gene in synergy with NF-κβ. Secreted INF-β activate JAK/STAT pathway by binding INF common receptor. As a result, INF-stimulated genes are induced. B) HCV attenuates innate immune responses at the multiple levels. NS3/4A protease inhibits RIG-I and TLR3 downstream pathway via blocking their adaptor molecules, IPS-1 and TRIF. HCV proteins NS5A and Core inhibit INF-stimulated gene expression by interfering with JAK/STAT pathway. HCV proteins E2 and NS5A inhibit PKR activation.
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Published in final edited form as: Rev Infect. 2010 July 1; 1(3): 151–157.
Regulation of host innate immunity by hepatitis C virus: crosstalk between hepatocyte and NK/DC Sung-Jae Park1,2 and Young S. Hahn1,3,4,* 1Beirne B Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA 2Department
of Internal Medicine, College of Medicine, Inje University, Busan, Korea
3Department
of Microbiology, University of Virginia, Charlottesville, VA 22908, USA
4Department
of Pathology, University of Virginia, Charlottesville, VA 22908, USA
Abstract NIH-PA Author Manuscript
Hepatitis C virus (HCV) infection in humans is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma. CD8+ T cells are involved in controlling HCV infection; but, in chronic HCV patients, severe CD4+ and CD8+ T cell dysfunction has been observed. This suggests that HCV may employ numerous mechanisms to counteract or possibly suppress the host T cell responses. The primary site of HCV replication occurs within hepatocytes in the liver. As a result of liver enodothelial cells perforated by fenestrations, parenchymal cells (hepatocytes) are not separated by a basal membrane, and thereby HCV-infected hepatocytes are extensively capable of interacting with innate immune cells including NK, DC. Recent studies reveal that the function of NK and DC function is significantly impaired in chronic HCV patients. Given a critical role of NK and DC in limiting HCV replication at the early phase of viral infection, it is likely that HCV-infected hepatocytes might be responsible for impairing NK and DC function by enhancing the expression of immunoregulatory molecules (either soluble or cell surface). Thus, this impairment of innate immunity attributes to the failure of generating effective T cell responses to clear HCV infection. In this article, we will review studies highlighting the regulation of innate immunity by HCV and crosstalk between hepatocytes and NK/DC in the hepatic environment.
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Keywords innate immunity; TLR activation; evasion of TLR signaling; the impaired function of NK; DC
Introduction Hepatitis C virus (HCV) infection is a growing public health problem and over 130 million people are chronically infected worldwide [1]. Unlike hepatitis B virus (HBV), HCV evades effective immune responses and establishes chronic infection in more than 80% of infected individuals. Persistent HCV infection predisposes to the increased incidence of complications such as liver cirrhosis and hepatocellular carcinoma [2]. Unfortunately a protective vaccine is not available and therapeutic options for HCV patients are still limited. Current standard therapy with pegylated interferon combined with ribavirin is often not tolerable because of side effects, and approximately half of individuals receiving anti-HCV
*
Corresponding author: [email protected].
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therapy mount a sustained virologic response (SVR). It is also worth-while to point out that, in spite of type I interferon (IFN) produced during acute infection, HCV replication is sustained and HCV infection fails to be cleared and establishes persistent infection. This suggests that HCV evolves multiple strategies to attenuate IFN-mediated antiviral mechanisms and counteract with host immune responses. An understanding of the mechanisms involved in HCV-mediated immune evasion strategies is a critical step to help the design of novel antiviral therapy and the development of vaccine. Hepatocytes are the primary target of HCV infection and replication. Hepatocytes comprise 70–80% of all liver cells and lie underneath the liver sinusoids collecting the blood from artery and intestine. Unlike most blood vessels, liver enodothelial cells do not form tight junctions and are perforated by fenestrations. Therefore, parenchymal cells are not separated by a basal membrane and there are extensive interactions of HCV-infected hepatocytes with immune cells, including NK and DC, as shown in Figure 1. Although early studies suggest that hepatocytes express low levels of class I MHC molecules, hepatocytes are emerging as an important player in regulating intrahepatic immune responses. In this review, we will provide a brief discussion of the HCV life cycle and describe the potential immunoregulatory mechanisms involving several cell types such as hepatocytes, NK, and DC from an immunological point of view.
The HCV life cycle NIH-PA Author Manuscript NIH-PA Author Manuscript
HCV is an enveloped positive stranded RNA virus belonging to the Flaviviridae family. The precise process by which HCV enters hepatocytes is not yet fully understood, but the entry of HCV may require lipoproteins and other cellular proteins [3]. Low density lipoprotein (LDL) receptor appears to be involved in endocytosis of HCV as antibodies to LDL receptor prevented HCV entry in a dose dependent manner and endocytosis of HCV is also competitively inhibited by LDL and very low density lipoprotein (VLDL), but not by high density lipoprotein (HDL) [4, 5]. In addition, HCV entry into hepatocytes is associated with other cellular proteins: the tetraspanin CD81, the scavenger receptor class B type I (SR-BI), and the tight junction proteins claudin-1, -6 or −9 [6–9]. While HCV entry appears to be reduced in the presence of antibodies to CD81, or the downregulation of CD81 in hepatoma cells [10], SR-BI is thought to be an additional factor to mediate the entry of HCV into cells [7, 11]. However, coexpression of CD81 and SR-BI are not sufficient for HCV entry, suggesting that other proteins are involved in HCV entry [6, 12]. Indeed, recent studies report that additional cellular factors such as the tight junction proteins, claudin 1 (CLDN1) and occludin are involved in the HCV entry [6, 13]. Nevertheless, certain cell types are still non-permissive despite the expression of CD81, SR-BI and CLDN1 and this indicates that additional unknown factor(s) may be necessary for the entry of HCV into hepatocytes [14]. Since several proteins have been identified as crucial factors for HCV entry, HCV entry occurs by the sequential steps of numerous cell surface molecules displayed in hepatocytes. After endocytosis, the positive strand HCV genome undergoes an uncoating process and is exposed to host cell machinery. The 5’ non-translated region of the HCV genome contains an internal ribosome entry site (IRESs). The viral genome is then translated as a polyprotein in the cytoplasm, and the HCV replication appears to occur in association with the endoplasmic reticulum. The individual structural (core, E1, E2) and non-structural proteins (NS2, NS3, NS4A, B, NS5A, B) are proteolytically processed from the poly-protein. To counteract with host immunity against HCV, viral proteins such as core, NS3A, NS5A, have been shown to inhibit the production of type I IFN as described below and play a role in the establishment of HCV persistent infection. Given the immunoregulatory role of type I IFN in activating innate immunity, particularly NK cell activation, the inhibition of the type I IFN response by HCV might directly be involved in the impaired innate and adaptive immunity as observed in chronic HCV patients.
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RIG-I/TLR activation and interference of RIG-I/TLR signaling by HCV NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Pathogen recognition receptors (PRRs) recognize constituents from microbial pathogens and trigger anti-viral responses by promoting the production of inflammatory cytokines. While HCV is able to activate toll like receptor3 (TLR3) and retinoic acid inducible gene I (RIG-I) pathway, several viral factors have been reported to inhibit the innate immune response and favors for virus survival [15, 16]. During HCV infection in hepatocytes, two PRRs (RIG-I, TLR3) recognize HCV RNA and trigger signaling cascades that lead to the synthesis of multiple cytokines, including type I IFNs and the activation of host defense mechanism (Figure 2A). RIG-I senses the poly-uridine motif of the HCV genome 3’ non-translated region in the cytoplasm recruits the adapter molecule INF-β promoter stimulator protein 1 (IPS-1) localized to the membrane of mitochondria [17, 18]. On the other hand, TLR3 senses double-stranded RNA in the endosome and recruits the adapter molecule Toll-IL-1 receptor domain-containing adapter inducing INF-β (TRIF) [19]. TRIF is essential for double-stranded RNA-stimulated synthesis of type 1 IFNs signaling. Nevertheless, both RIG-I and TLR3 pathways initiate a signaling cascade that result in INF-β synthesis [19, 20]. Secreted INF-β then activates the JAK/STAT signaling cascade by binding to the INFα/β receptor [19]. This cascade results in the transcription of IFN-stimulating genes (ISGs) including protein kinase R (PKR), 2’,5’ oligoadenylate synthetases-RNaseL [21–24]. These products play a pivotal role in limiting virus infection by suppressing viral replication and modulating adaptive immune response [25]. As a counteractive mechanism for TLR-induced anti-viral responses, HCV develops strategies to evade these immune responses in part through its ability to antagonize signaling to the IFN response at multiple levels (Figure 2B). First, the HCV NS3/4A protease inactivates IPS-1 by cleaving and delocalizing from the mitochondria membrane, thus preventing RIG-I signaling [11, 17, 26]. Importantly, liver tissues from chronic infected HCV patients demonstrated redistribution of IPS-1, which provides strong evidence that IPS-1 is targeted and is an essential component of IFN transcription [27]. In addition, NS3/4A protease has also been demonstrated to disrupt TLR3 pathway by accelerating degradation of TRIF in vitro [28]. As a consequence of cleavage of IPS-1 and TRIF by NS3/4A, IFN synthesis is reduced in HCV-infected cells, and the host defense mechanism is likely to be impaired [11]. It suggests that the protease inhibitors, which are now in clinical trial, may not only reduce viral replication, but also restore host immunity [11]. Second, HCV core inhibits IFN signaling by interfering with JAK/STAT pathway [29] whereas HCV NS5A blocks 2’–5’ oligoadenylate synthetase (2’–5’ OAS) and induces IL-8, which inhibits overall ISG expression [19, 30]. Lastly, HCV E2 and NS5A inhibit PKR, which leads to increase the phosphorylation of eIF2α and inhibits protein synthesis in infected cells [31, 32]. The analysis of PKR activation among various HCV genotypes demonstrated that HCV genotype 1 is relatively resistant to IFN therapy and inhibits PKR more efficiently than HCV genotype 2 and 3 [32, 33]. These findings provide an explanation to why patients with genotype 2 and 3 have a greater SVR rate than those with genotype 1. As these viral escape mechanisms have been identified in cell culture systems, more data wait for demonstrating their physiological relevance during a natural HCV infection. Given a crucial role of type I IFN in the activation of NK cells, the inhibition of type I IFN synthesis by HCV proteins might be critical for impairing the function of NK and DC shown in chronic HCV patients as described below. Further studies are necessary to elucidate the potential role of HCV-induced inhibition of type I IFN synthesis in impairing NK cell activation, resulting in affecting DC activation via NK-DC crosstalk.
Inhibition of NK antiviral activity by HCV Natural Killer (NK) cells are enriched in the liver and constitute the first line of host defense mechanisms against pathogen [34]: the intrahepatic lymphocytes contain 37% NK cells
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compare to 13% NK cells present in the peripheral blood [35]. Following viral infection, NK cells can penetrate the endothelial cells, enter the space of Disse, and directly contact the microvilli of hepatocytes. NK cells activated during the early stages of viral infection play a pivotal role in guiding first defense against viral infection and linking between innate and adaptive responses. NK cell function is modulated by the expression of inhibitory receptors (Ig-like killer inhibitory receptor, CD94/NKG2 receptors) and activating receptors (NKp46, NKp30, NKp44, NKG2D). During the early stage of HCV infection, NK cells are activated by type I IFNs and DCs [36, 37] and the activated NK cells can inhibit HCV infection by killing HCV-infected hepatocytes directly, secreting cytokines such as IFN-γ that inhibit HCV replication and stimulating adaptive immune response [38–43]. Thus, NK cells play an important role in controlling acute HCV infection [43]. However, the frequency of NK cells is decreased in peripheral blood of chronic HCV infected patients [44, 45]. Interestingly, patients who cleared HCV with antiviral therapy showed similar frequency NK cells compared to healthy controls [44], and intrahepatic NK cells also correlate positively with sustained response to IFN/ribavirin treatment for chronic HCV patients [46]. Notably, in chronic HCV patients, NK cells are functionally impaired and the ability of NK cells to augment DC function is severely compromised [38, 47]. These results suggest that HCV evades NK cell surveillance via multiple mechanisms. The binding of the HCV envelope protein, HCV-E2, to CD81 (an ubiquitous cellular receptor for HCV) has been reported to block NK cell activation with inhibition of IFN-γ production, and cytotoxic granule release [48, 49]. In addition, the expression of HCV core protein at hepatocytes enhances the expression of HLA-E, a ligand of NK cell inhibitory receptor NKG2A, and inhibits NK cells function [50, 51]. Thus, it is likely that the intracellular HCV core alters the expression of NK cell receptor repertoire, favoring expansion of NK inhibitory receptors. Although most of in vitro cell culture experiments and clinical studies suggest that NK cells play a critical role in controlling HCV infection, the development of reliable in vivo models is an essential step to clarify the function of NK cells in the complex network of innate and adaptive immune responses. Importantly, recent studies reported that NK cells can crosstalk with DC, resulting in the regulation of adaptive T cell responses. Thus, it is possible that the impaired DC function as described below might be as a result of the inhibition of NK cell activation in chronic HCV patients.
Impairment of DC function by HCV
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Antigen-presenting cells, such as DC, have an important role in initiating immune responses to viral infection and also express different TLR, thus responding to diverse pathogens [52]. Importantly, DC play a crucial role in linking the innate immunity to the adaptive immunity by presenting viral antigens to T cells [53]. Impairment of DC can severely disrupt the ability of the host immune response to clear viral infection, thereby resulting in ongoing viral infection. Numerous studies have also reported that patients with chronic HCV infection have decreased numbers of peripheral myeloid and plasmacytoid DC [35, 54–56]. This could be possibly due to the migration of DC from the peripheral blood to the infected liver. This possibility is further supported by recent studies that intrahepatic accumulation of DC in chronic HCV hepatitis patients is increased markedly compared to normal control liver specimens [57]. However, the intrahepatic trapping of DC may not be specific to chronic HCV infection, as this has been shown in another liver-tropic viral infection, i.e. chronic HBV infection. Human DCs are classified into two major subsets: myeloid DCs and plasmacytoid DCs [52, 58–60]. Myeloid DCs are considered as classical APCs, as they are able to initiate the activation of naïve and effector T cells. Thus, defective myeloid DC function could result in insufficient Th1 cell development. Notably, in chronic HCV patients, the ability of myeloid DCs to stimulate allogeneic T cells is diminished [54, 61, 62]. Myeloid DCs from chronic HCV patients display increased IL-10 and decreased IL-12 production in response to stimulation such as poly(I:C) or CD40 [54, 61–64]. As one of viral Rev Infect. Author manuscript; available in PMC 2014 March 29.
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factor(s) to impair DC function, extracellular HCV core has been reported to inhibit the production of IL-12 by human myeloid DCs in response to TLR stimulation [65]. Based on the pivotal role of cytokines (i.e. type I IFN, IL-12) secreted by DC in NK activation during the early phase of viral infection, future studies are necessary for paying attention to elucidate the contribution of impaired DC function in chronic HCV patients on altering NK cell activation. Importantly, plasmacytoid DC play a pivotal role in generating anti-viral responses by secretion of high levels of IFN-α in response to TLR7 and TLR9 stimulation [66, 67]. In HCV infection, the function of plasmacytoid DCs is impaired compared to healthy control and their ability to produce IFN-α upon in vitro stimulation is reduced [54, 56, 61, 68–70]. Interestingly, patients who resolved their HCV infection spontaneously and patients who responded to therapy showed similar numbers of plasmacytoid DC and IFN-α production as the healthy control group [56, 68]. Taken together, the impaired DC function in HCV patients might explain a failure in generating effective T cell responses during HCV infection. Given that inflammatory cytokines, particularly IL-12, are crucial for activating NK cells, it is possible that the inhibition of such cytokines might be also involved in the inhibition of NK cell activation as described above.
Future Studies
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HCV utilized several mechanisms related to escape innate and adaptive immune responses at multiple steps. HCV needs these strategies including disruptions of mediators in intracellular antiviral defenses, as well as interruptions of host immune processes, for survival in the host. Although our understanding at the molecular level that HCV may evade detection and clearance by the host immune system was advanced after the cell culture system was developed, the potential mechanisms to clinical persistent infection still remain to be defined. In addition to recent advances in cell biology and immunology of the host, it is hoped that small animal models will be developed to allow evaluation of antiviral agents, vaccines, and immunotherapies. And the benefits of such advances might help patients who suffer from serious forms of liver disease with improved personal life, and it may ultimately become possible to provide protection against viral infection. Furthermore, although several aspects of immune responses are not functional during chronic HCV infection, the initial causal factor(s) responsible for impaired responses to HCV has yet to be determined. Given that NK and DC recruited to infection sites following viral infection lead to the promotion of NK-DC cross-talk, influencing CD8+ T cell responses, it is critical for a better understanding of the mechanisms of hepatic NK cell function and the cooperation between hepatic NK cells and other cells (i.e. DC, CD8+ T cells) in the liver.
Acknowledgments NIH-PA Author Manuscript
We thank the members of Hahn laboratory for helpful discussions. This work was supported by the GlaxoSmithKline Research Fund of the Korean Association for the Study of the Liver and the Inje University in 2006 to SJP, and NIH R01DK066754, U19AI063222 to YSH.
Abbreviations HCV
heptatitis C virus
NK
natural killer cells
DC
dendritic cells
References 1. Global burden of disease (GBD) for hepatitis C. J Clin Pharmacol. 2004; 44:20–29.
Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
Page 6
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
2. Davis GL, Albright JE, Cook SF, Rosenberg D. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003; 9:331–338. 3. Burlone ME, Budkowska A. Hepatitis C virus cell entry: role of lipoproteins and cellular receptors. J Gen Virol. 2009; 90:1055–1070. 4. Agnello V, Abel G, Elfahal M, Knight GB, Zhang QX. Hepatitis C virus and other flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1999; 96:12766– 12771. 5. Petit JM, Minello A, Duvillard L, Jooste V, Monier S, Texier V, Bour JB, Poussier A, Gambert P, Verges B, Hillon P. Cell surface expression of LDL receptor in chronic hepatitis C: correlation with viral load. Am J Physiol Endocrinol Metab. 2007; 293:E416–E420. 6. Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B, Hatziioannou T, McKeating JA, Bieniasz PD, Rice CM. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature. 2007; 446:801–805. 7. Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G, Traboni C, Nicosia A, Cortese R, Vitelli A. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. Embo J. 2002; 21:5017–5025. 8. Zhang J, Randall G, Higginbottom A, Monk P, Rice CM, McKeating JA. CD81 is required for hepatitis C virus glycoprotein-mediated viral infection. J Virol. 2004; 78:1448–1455. 9. Zheng A, Yuan F, Li Y, Zhu F, Hou P, Li J, Song X, Ding M, Deng H. Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus. J Virol. 2007; 81:12465–12471. 10. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S. Binding of hepatitis C virus to CD81. Science. 1998; 282:938–941. 11. Sklan EH, Charuworn P, Pang PS, Glenn JS. Mechanisms of HCV survival in the host. Nat Rev Gastroenterol Hepatol. 2009; 6:217–227. 12. Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM, McKeating JA. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci U S A. 2003; 100:7271–7276. 13. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP, Rice CM. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature. 2009; 457:882–886. 14. Moradpour D, Penin F, Rice CM. Replication of hepatitis C virus. Nat Rev Microbiol. 2007; 5:453–463. 15. Gale M Jr, Foy EM. Evasion of intracellular host defence by hepatitis C virus. Nature. 2005; 436:939–945. 16. Wohnsland A, Hofmann WP, Sarrazin C. Viral determinants of resistance to treatment in patients with hepatitis C. Clin Microbiol Rev. 2007; 20:23–38. 17. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, Gale M Jr. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci U S A. 2005; 102:2986–2991. 18. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr. Innate immunity induced by compositiondependent RIG-I recognition of hepatitis C virus RNA. Nature. 2008; 454:523–527. 19. Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence. J Clin Invest. 2009; 119:1745–1754. 20. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008; 1143:1–20. 21. Guo JT, Sohn JA, Zhu Q, Seeger C. Mechanism of the interferon alpha response against hepatitis C virus replicons. Virology. 2004; 325:71–81. 22. Hui DJ, Bhasker CR, Merrick WC, Sen GC. Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2.GTP.Met-tRNAi. J Biol Chem. 2003; 278:39477–39482. 23. Pflugheber J, Fredericksen B, Sumpter R Jr, Wang C, Ware F, Sodora DL, Gale M Jr. Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc Natl Acad Sci U S A. 2002; 99:4650–4655.
Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
Page 7
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
24. Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM. New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. J Virol. 2005; 79:6291–6298. 25. Sen GC. Viruses and interferons. Annu Rev Microbiol. 2001; 55:255–281. 26. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A. 2005; 102:17717–17722. 27. Loo YM, Owen DM, Li K, Erickson AK, Johnson CL, Fish PM, Carney DS, Wang T, Ishida H, Yoneyama M, Fujita T, Saito T, Lee WM, Hagedorn CH, Lau DT, Weinman SA, Lemon SM, Gale M Jr. Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci U S A. 2006; 103:6001–6006. 28. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, Ikeda M, Ray SC, Gale M Jr, Lemon SM. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A. 2005; 102:2992–2997. 29. Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Haussinger D. IFN-alpha antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. Faseb J. 2003; 17:488–490. 30. Polyak SJ, Khabar KS, Paschal DM, Ezelle HJ, Duverlie G, Barber GN, Levy DE, Mukaida N, Gretch DR. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol. 2001; 75:6095–6106. 31. Gale MJ Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997; 230:217–227. 32. Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science. 1999; 285:107–110. 33. Noguchi T, Satoh S, Noshi T, Hatada E, Fukuda R, Kawai A, Ikeda S, Hijikata M, Shimotohno K. Effects of mutation in hepatitis C virus nonstructural protein 5A on interferon resistance mediated by inhibition of PKR kinase activity in mammalian cells. Microbiol Immunol. 2001; 45:829–840. 34. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001; 1:41–49. 35. Szabo G, Chang S, Dolganiuc A. Altered innate immunity in chronic hepatitis C infection: cause or effect? Hepatology. 2007; 46:1279–1290. 36. Ebihara T, Shingai M, Matsumoto M, Wakita T, Seya T. Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T cells and natural killer cells. Hepatology. 2008; 48:48–58. 37. Shin EC, Seifert U, Kato T, Rice CM, Feinstone SM, Kloetzel PM, Rehermann B. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J Clin Invest. 2006; 116:3006–3014. 38. Ahmad A, Alvarez F. Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis. J Leukoc Biol. 2004; 76:743–759. 39. Frese M, Schwarzle V, Barth K, Krieger N, Lohmann V, Mihm S, Haller O, Bartenschlager R. Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology. 2002; 35:694–703. 40. Golden-Mason L, Rosen HR. Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transpl. 2006; 12:363–372. 41. Larkin J, Bost A, Glass JI, Tan SL. Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons. J Interferon Cytokine Res. 2006; 26:854– 865. 42. Wang SH, Huang CX, Ye L, Wang X, Song L, Wang YJ, Liang H, Huang XY, Ho WZ. Natural killer cells suppress full cycle HCV infection of human hepatocytes. J Viral Hepat. 2008; 15:855– 864. 43. Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol. 2009; 86:513–528. 44. Morishima C, Paschal DM, Wang CC, Yoshihara CS, Wood BL, Yeo AE, Emerson SS, Shuhart MC, Gretch DR. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology. 2006; 43:573–580. Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
Page 8
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
45. Nattermann J, Feldmann G, Ahlenstiel G, Langhans B, Sauerbruch T, Spengler U. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut. 2006; 55:869–877. 46. Yamagiwa S, Matsuda Y, Ichida T, Honda Y, Takamura M, Sugahara S, Ishikawa T, Ohkoshi S, Sato Y, Aoyagi Y. Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells. Hepatol Res. 2008; 38:664–672. 47. Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T, Kanazawa Y, Hiramatsu N, Hayashi N. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol. 2004; 173:6072–6081. 48. Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S, D'Oro U, Mosca M, Filliponi F, Brunetto RM, Bonino F, Abrignani S, Valiante NM. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med. 2002; 195:35–41. 49. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med. 2002; 195:43–49. 50. Nattermann J, Nischalke HD, Hofmeister V, Ahlenstiel G, Zimmermann H, Leifeld L, Weiss EH, Sauerbruch T, Spengler U. The HLA-A2 restricted T cell epitope HCV core 35–44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells. Am J Pathol. 2005; 166:443–453. 51. Schulte D, Vogel M, Langhans B, Kramer B, Korner C, Nischalke HD, Steinberg V, Michalk M, Berg T, Rockstroh JK, Sauerbruch T, Spengler U, Nattermann J. The HLA-E(R)/HLA-E(R) genotype affects the natural course of hepatitis C virus (HCV) infection and is associated with HLA-E-restricted recognition of an HCV-derived peptide by interferon-gamma-secreting human CD8(+) T cells. J Infect Dis. 2009; 200:1397–1401. 52. Liu B, Woltman AM, Janssen HL, Boonstra A. Modulation of dendritic cell function by persistent viruses. J Leukoc Biol. 2009; 85:205–214. 53. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S. Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol. 2002; 20:621–667. 54. Kanto T, Inoue M, Miyatake H, Sato A, Sakakibara M, Yakushijin T, Oki C, Itose I, Hiramatsu N, Takehara T, Kasahara A, Hayashi N. Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection. J Infect Dis. 2004; 190:1919–1926. 55. Tsubouchi E, Akbar SM, Murakami H, Horiike N, Onji M. Isolation and functional analysis of circulating dendritic cells from hepatitis C virus (HCV) RNA-positive and HCV RNA-negative patients with chronic hepatitis C: role of antiviral therapy. Clin Exp Immunol. 2004; 137:417–423. 56. Wertheimer AM, Bakke A, Rosen HR. Direct enumeration and functional assessment of circulating dendritic cells in patients with liver disease. Hepatology. 2004; 40:335–345. 57. Nattermann J, Zimmermann H, Iwan A, von Lilienfeld-Toal M, Leifeld L, Nischalke HD, Langhans B, Sauerbruch T, Spengler U. Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C. Hepatology. 2006; 44:945–954. 58. O'Doherty U, Pen M, Gezelter S, Swiggard WJ, Betjes M, Bhardwaj N, Steinman RM. Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology. 1994; 82:487–493. 59. Robinson SP, Patterson S, English N, Davies D, Knight SC, Reid CD. Human peripheral blood contains two distinct lineages of dendritic cells. Eur J Immunol. 1999; 29:2769–2778. 60. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, Antonenko S, Liu YJ. The nature of the principal type 1 interferon-producing cells in human blood. Science. 1999; 284:1835–1837. 61. Averill L, Lee WM, Karandikar NJ. Differential dysfunction in dendritic cell subsets during chronic HCV infection. Clin Immunol. 2007; 123:40–49. 62. Kanto T, Inoue M, Miyazaki M, Itose I, Miyatake H, Sakakibara M, Yakushijin T, Kaimori A, Oki C, Hiramatsu N, Kasahara A, Hayashi N. Impaired function of dendritic cells circulating in
Rev Infect. Author manuscript; available in PMC 2014 March 29.
Park and Hahn
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NIH-PA Author Manuscript NIH-PA Author Manuscript
patients infected with hepatitis C virus who have persistently normal alanine aminotransferase levels. Intervirology. 2006; 49:58–63. 63. Della Bella S, Crosignani A, Riva A, Presicce P, Benetti A, Longhi R, Podda M, Villa ML. Decrease and dysfunction of dendritic cells correlate with impaired hepatitis C virus-specific CD4+ T-cell proliferation in patients with hepatitis C virus infection. Immunology. 2007; 121:283–292. 64. Rodrigue-Gervais IG, Jouan L, Beaule G, Sauve D, Bruneau J, Willems B, Sekaly RP, Lamarre D. Poly(I:C) and lipopolysaccharide innate sensing functions of circulating human myeloid dendritic cells are affected in vivo in hepatitis C virus-infected patients. J Virol. 2007; 81:5537–5546. 65. Waggoner SN, Hall CH, Hahn YS. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. J Leukoc Biol. 2007; 82:1407–1419. 66. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001; 194:863–869. 67. Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005; 23:275–306. 68. Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, Szabo G. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol. 2006; 177:6758–6768. 69. Shiina M, Rehermann B. Cell culture-produced hepatitis C virus impairs plasmacytoid dendritic cell function. Hepatology. 2008; 47:385–395. 70. Ulsenheimer A, Gerlach JT, Jung MC, Gruener N, Wachtler M, Backmund M, Santantonio T, Schraut W, Heeg MH, Schirren CA, Zachoval R, Pape GR, Diepolder HM. Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection. Hepatology. 2005; 41:643–651.
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Fig 1.
A diagram for the liver sinusoid. Under the normal condition, due the physical barrier formed by portal endothelial cells and basal membrane, innate immune cells, in particular, immature DC are easily not accessible to interact with hepatocytes. However, following the inflammatory stimuli including liver tropic HCV infection, NK and DC can direct contact with HCV-infected hepatocytes due to the increased permeabilization of endothelia membrane. So there are extensive interactions between HCV-infected hepatocytes and NK/ DC. These interaction might play a critical role in regulating antiviral T cell responses.
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Fig 2.
A) Pathogen recognition receptors RIG-I and TLR3 detect HCV ds RNA and activate via their adaptor molecules IPS-1 and TRIF. These signaling cascades result in transcription of INF-β gene in synergy with NF-κβ. Secreted INF-β activate JAK/STAT pathway by binding INF common receptor. As a result, INF-stimulated genes are induced. B) HCV attenuates innate immune responses at the multiple levels. NS3/4A protease inhibits RIG-I and TLR3 downstream pathway via blocking their adaptor molecules, IPS-1 and TRIF. HCV proteins NS5A and Core inhibit INF-stimulated gene expression by interfering with JAK/STAT pathway. HCV proteins E2 and NS5A inhibit PKR activation.
Rev Infect. Author manuscript; available in PMC 2014 March 29.
