Hepatitis: Shata MT

Shata MT, Navaneethan U. · No affiliation provided · Clin Infect Dis. · Pubmed #18781881 No free full text.

This publication has no abstract.

Navaneethan U, Al Mohajer M, Shata MT. · Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA. · Liver Int. · Pubmed #18662274 No free full text.

Abstract: Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale epidemics of acute viral hepatitis, particularly in developing countries. In men and non-pregnant women, the disease is usually self-limited and has a case-fatality rate of less than <0.1%. However, in pregnant women, particularly from certain geographical areas in India, HEV infection is more severe, often leading to fulminant hepatic failure and death in a significant proportion of patients. In contrast, reports from Egypt, Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in non-pregnant women. The reasons for this geographical difference are not clear. The high mortality rate in pregnancy has been thought to be secondary to the associated hormonal (oestrogen and progesterone) changes during pregnancy and consequent immunological changes. These immunological changes include downregulation of the p65 component of nuclear factor (NF-kappaB) with a predominant T-helper type 2 (Th2) bias in the T-cell response along with host susceptibility factors, mediated by human leucocyte antigen expression. Thus far, researchers were unable to explain the high HEV morbidity in pregnancy, why it is different from other hepatitis viruses such as hepatitis A with similar epidemiological features and the reason behind the difference in HEV morbidity in pregnant women in different geographical regions. The recent developments in understanding the immune response to HEV have encouraged us to review the possible mechanisms for these differences. Further research in the immunology of HEV and pregnancy is required to conquer this disease in the near future.

Blackard JT, Shata MT, Shire NJ, Sherman KE. · Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · Hepatology. · Pubmed #18161707 links to  free full text

This publication has no abstract.

Prince AM, Shata MT. · Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA. · Clin Liver Dis. · Pubmed #11685797 No free full text.

Abstract: Because hepatitis C virus is etiologically involved in about half the cases of the world's most common cancer, hepatocellular carcinoma, and because this virus is likely to continue to spread in most of the developing world for many years, the authors believe that development of a prophylactic vaccine is imperative. Numerous approaches are available to overcome the many impediments which make the development of an HCV vaccine difficult. Such impediments include the many viral genotypes and quasispecies of HCV and the association of virions with host lipids. It is likely that overcoming these impediments will require a vaccine which induces a strong cell-mediated response. The most promising approach seems to be DNA-based immunization or a prime-boost regimen with DNA priming and boosting with a viral vector. Potentiation of responses with adjuvant strategies will probably be necessary. Hepatitis C virus immunization is in an early stage of development. Given the explosive growth in the understanding of immunology, progress should be rapid.

Atiq M, Shire NJ, Barrett A, Rouster SD, Sherman KE, Shata MT. · University of Cincinnati, Cincinnati, OH 45267, USA. · Emerg Infect Dis. · Pubmed #19239770 links to  free full text

Abstract: In the United States, the seroprevalence rate for hepatitis E virus (HEV) is approximately 20%. This study examined HEV seroprevalence in persons with and without chronic liver disease. Our data indicate that HEV seropositivity is high in patients with chronic liver disease and that HEV seroprevalence increases significantly with age.

Youn JW, Hu YW, Tricoche N, Pfahler W, Shata MT, Dreux M, Cosset FL, Folgori A, Lee DH, Brotman B, Prince AM. · Laboratory of Virology, The Lindsley F Kimball Research Institute of the New York Blood Center, New York, New York 10065, USA. · J Virol. · Pubmed #18753204 links to  free full text

Abstract: Given the failures of nonreplicating vaccines against chronic hepatitis C virus (HCV) infection, we hypothesized that a replicating viral vector may provide protective immunity. Four chimpanzees were immunized transdermally twice with recombinant vaccinia viruses (rVV) expressing HCV genes. After challenge with 24 50% chimpanzee infective doses of homologous HCV, the two control animals that had received only the parental VV developed chronic HCV infection. All four immunized animals resolved HCV infection. The difference in the rate of chronicity between the immunized and the control animals was close to statistical significance (P = 0.067). Immunized animals developed vigorous gamma interferon enzyme-linked immunospot responses and moderate proliferative responses. To investigate cross-genotype protection, the immunized recovered chimpanzees were challenged with a pool of six major HCV genotypes. During the acute phase after the multigenotype challenge, all animals had high-titer viremia in which genotype 4 dominated (87%), followed by genotype 5 (13%). However, after fluctuating low-level viremia, the viremia finally turned negative or persisted at very low levels. This study suggests the potential efficacy of replicating recombinant vaccinia virus-based immunization against chronic HCV infection.

Velilla PA, Shata MT, Lages CS, Ying J, Fichtenbaum CJ, Chougnet C. · Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA. · AIDS Res Hum Retroviruses. · Pubmed #18275348 No free full text.

Abstract: We evaluated the effect of low-dose IL-2 therapy (daily 1.2 MIU/m(2), subcutaneously) on the number and phenotype of regulatory T cells (T(regs)) and natural killer (NK) cells in HIV/HCV-coinfected patients taking antiretroviral therapy. The frequency and phenotype of circulating T(regs) (defined as CD3(+) CD4(+) CD25(high) or CD3(+) CD4(+) FOXP3(+)) and NK cells (CD3(-) CD16(+)/CD56(+)) were evaluated at baseline and after 12 weeks of treatment. The expression of CD25, CTLA-4, and granzymes A and B by CD4(+) FOXP3(+) cells, as well as the expression of KIR receptors (NKB1, CD158a, and NKAT2) on NK cells, was evaluated. Low doses of IL-2 resulted in the augmented frequency and absolute number of T(regs) in coinfected individuals. FOXP3 levels per cell as well as augmented CD25 and CTLA-4 expression by T(regs) suggested that IL-2 may lead to both expansion and activation of T(regs), although changes in the proportion of CD4(+) FOXP3(+) cells were not associated with changes in HCV viral load and CD4(+) cells between baseline and week 12. NK cell frequency also increased after IL-2 therapy. Interestingly, the pattern of expression of KIR receptors was changed by IL-2 treatment, since the frequency of NK cells expressing NKB1 augmented whereas the frequency of NK expressing CD158a and NKAT2 decreased.

Shata MT, Barrett A, Shire NJ, Abdelwahab SF, Sobhy M, Daef E, El-Kamary SS, Hashem M, Engle RE, Purcell RH, Emerson SU, Strickland GT, Sherman KE. · Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45267-0595, USA. · J Immunol Methods. · Pubmed #17905301 links to  free full text

Abstract: In developing countries, hepatitis E (HEV) and hepatitis A (HAV) are the major causes of acute viral hepatitis with similar feco-oral modes of transmission. In contrast to the high seroprevalence of hepatitis A infection, a low seroprevalence of HEV among children in endemic areas has been reported. These data suggest the possibility that silent HEV infection is undiagnosed by the current available methods. Many of the serological tests used for HEV diagnosis have poor specificity and are unable to differentiate among different genotypes of HEV. Moreover, the RT-PCR used for HEV isolation is only valid for a brief period during the acute stage of infection. Cell-mediated immune (CMI) responses are highly sensitive, and long lasting after sub-clinical infections as shown in HCV and HIV. Our objective was to develop a quantitative assay for cell-mediated immune (CMI) responses in HEV infection as a surrogate marker for HEV exposure in silent infection. Quantitative assessment of the CMI responses in HEV will also help us to evaluate the role of CMI in HEV morbidity. In this study, an HEV-specific interferon-gamma (IFN-gamma) ELISPOT assay was optimized to analyze HEV-specific CMI responses. We used peripheral blood mononuclear cells (PBMC) and sera from experimentally infected chimpanzees and from seroconverted and control human subjects to validate the assay. The HEV-specific IFN-gamma ELISPOT responses correlated strongly and significantly with anti-HEV ELISA positive/negative results (rho=0.73, p=0.02). Moreover, fine specificities of HEV-specific T cell responses could be identified using overlapping HEV ORF2 peptides.

Shata MT, Pfahler W, Brotman B, Lee DH, Tricoche N, Murthy K, Prince AM. · Laboratory of Virology, Lindsley F. Kimball Research Institute of the New York Blood Center, New York, NY 10021, USA. · J Med Primatol. · Pubmed #16764675 links to  free full text

Abstract: BACKGROUND: We previously reported successful therapeutic immunization in a chimpanzee having a relatively low viral load, which was immunized with recombinant plasmid hepatitis B surface antigen (HBsAg) DNA and boosted with recombinant HBsAg encoding canarypox virus. In the present study, we attempted to confirm these findings in an animal with a high virus load. METHODS AND RESULTS: We tested three immunization strategies successively over a 3-year period. In the first of these, we administered four monthly injections of DNA encoding HBsAg + PreS2 + hepatitis B core antigen (HBcAg) + DNA encoding interleukin (IL)-12, (given 3 days later), and boosted with canarypox expressing all of the above HBV genes 6 months after initial immunization. No reduction in viral load was observed. In the second trial, we administered lamivudine for 8 weeks, and then began monthly DNA-based immunization with plasmids expressing the above viral genes; however, viral loads rebounded 1 week after termination of lamivudine therapy. In a third trial, we continued lamivudine therapy for 30 weeks and immunized with vaccinia virus expressing the above viral genes 18 and 23 weeks after the start of lamivudine therapy. Again viral loads rebounded shortly after cessation of lamivudine treatment. Analysis of cell-mediated immune responses, and their avidity, revealed that DNA-based immunization produced the strongest enhancement of high avidity T-cell responses, while recombinant vaccinia immunization during lamivudine therapy enhanced low avidity responses only. The strongest low and high avidity responses were directed to the middle surface antigen. CONCLUSIONS: Three strategies for therapeutic immunization failed to control HBV viremia in a chronically infected chimpanzee with a high viral load.

Youn JW, Park SH, Lavillette D, Cosset FL, Yang SH, Lee CG, Jin HT, Kim CM, Shata MT, Lee DH, Pfahler W, Prince AM, Sung YC. · National Research Laboratory of DNA Medicine, Division of Molecular and Life Science, POSTECH Biotech Center, Pohang University of Science and Technology, Republic of Korea. · Hepatology. · Pubmed #16317673 No free full text.

Abstract: Immune correlates of protection against hepatitis C virus (HCV) infection are not well understood. Here we investigated 2 naive and 6 immunized chimpanzees before and after intravenous challenge, 12 weeks after the last immunization, with 100 50% chimpanzee infectious doses (CID(50)) of heterologous genotype 1b HCV. Vaccination with recombinant DNA and adenovirus vaccines expressing HCV core, E1E2, and NS3-5 genes induced long-term HCV-specific antibody and T-cell responses and reduced peak viral load about 100 times compared with controls (5.91 +/- 0.38 vs. 3.81 +/- 0.71 logs, respectively). There was a statistically significant inverse correlation between peak viral loads and envelope glycoprotein 2 (E2)-specific antibody responses at the time of challenge. Interestingly, one vaccinee that had sterilizing immunity against slightly heterologous virus generated the highest level of E2-specific total and neutralizing antibody responses as well as strong NS3/NS5-specific T-cell proliferative responses. The other four vaccinees with low levels of E2-specific antibody had about 44-fold reduced peak viral loads but eventually developed persistent infections. In conclusion, vaccine-induced E2-specific antibody plays an important role in prevention from nonhomologous virus infection and may provide new insight into the development of an effective HCV vaccine.

Prince AM, Brotman B, Lee DH, Pfahler W, Tricoche N, Andrus L, Shata MT. · Laboratory of Virology, Lindsley F. Kimball Research Institute, New York Blood Center, NY 10021, USA. · J Infect Dis. · Pubmed #16235167 No free full text.

Abstract: An open question for hepatitis C virus (HCV) vaccine development is whether the various genotypes of this virus protect against the development of chronic infection after heterologous infection with different genotypes. We approached this question by challenging chimpanzees that had recovered from HCV genotype 1a or 1b infection with 6 heterologous genotypes as well as with a homologous genotype (for chimpanzees originally infected with genotype 1a). All 9 chimpanzees rechallenged with a homologous genotype developed self-limited infections. Of 11 chimpanzees challenged with 100 chimpanzee infectious doses of heterologous genotypes, 6 developed self-limited infections, with peak viral loads in acute-phase serum that were ~5-fold lower than those seen during primary infections. One chimpanzee (which had recovered from genotype 1b infection and was rechallenged with genotype 6a) did not develop viremia but did show an anamnestic cell-mediated immune response after rechallenge. Four of the 11 chimpanzees rechallenged with heterologous genotypes developed chronic infections with the genotypes used for rechallenge. These findings suggest that a universally protective HCV vaccine may need to incorporate epitopes from multiple genotypes.

Al-Sherbiny M, Osman A, Mohamed N, Shata MT, Abdel-Aziz F, Abdel-Hamid M, Abdelwahab SF, Mikhail N, Stoszek S, Ruggeri L, Folgori A, Nicosia A, Prince AM, Strickland GT. · Egyptian Reference Diagnostic Center, VACSERA, Cairo, Egypt. · Am J Trop Med Hyg. · Pubmed #16014830 links to  free full text

Abstract: Sporadic cases of cell-mediated immunity (CMI) in persons exposed to hepatitis C (HCV) but evidently uninfected have been reported. To further define this, we measured CMI in individuals without evidence of HCV infection, that is, negative for HCV-antibodies (anti-HCV) and RNA, residing in a rural Egyptian community where prevalence of anti-HCV was 24%. Cell-mediated immunity (CMI) measured by interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay, confirmed by intracellular staining using flow cytometry, against HCV peptides was measured in seronegative individuals with high-risk (HR) and low-risk (LR) exposures to HCV. Thirteen of 71 (18.3%) HR subjects but only 1 of 35 (2.9%) LR subjects had detectable CMI (P = 0.032). These data are compatible with the hypothesis that exposures to HCV may lead to development of HCV-specific CMI without anti-HCV and ongoing viral replication. We speculate induced CMI clears HCV sometimes when anti-HCV is not detectable, and HCV-specific CMI is a useful surrogate marker for exposure to HCV.

Farid A, Al-Sherbiny M, Osman A, Mohamed N, Saad A, Shata MT, Lee DH, Prince AM, Strickland GT. · Egyptian Reference Diagnostic Center, Dokki, Giza, Egypt. · Parasite Immunol. · Pubmed #15987342 No free full text.

Abstract: Patients coinfected with hepatitis C virus (HCV) and the trematode, Schistosoma mansoni, have an increased incidence of viral persistence and accelerated fibrosis. To investigate immunological mechanisms responsible for this more aggressive natural history of HCV, the core HCV-specific T-cell responses were analysed in 44 donated blood units rejected because they had antibodies to HCV (anti-HCV). Half also had anti-S. mansoni antibodies, evidence of past or active infection. HCV-specific ELISPOT responses were examined using pools of 180 overlapping 9-mer peptides with offsets of one covering the core of HCV genotype 4a. Comparison of T-cell responses in blood units positive for both anti-HCV and anti-Schistosoma antibodies with blood units positive only for anti-HCV antibodies showed a significant decrease in core-specific T-cell IFN-gamma (505+/- 46 vs. 803 +/- 66 ISC/10(6) cells, P < 0.001), IL-4 (2 +/- 108 vs. 641 +/- 131 ISC/10(6) cells, P < 0.001), and IL-10 (159 +/- 105 vs. 466 +/- 407 ISC/10(6) cells, P < 0.002) responses. In contrast, there was no significant difference in cell-mediated immune response (CMI) to PHA mitogen between these two groups. Therefore, we concluded T cells from persons with anti-Schistosoma have reduced IFN-gamma, IL-4, and IL-10 secreting HCV-specific T-cell responses. This may explain why Schistosoma coinfection increases persistence and severity of HCV infection.

Sun J, Li K, Shata MT, Chan TS. · Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1019, USA. · Curr Opin Gastroenterol. · Pubmed #15703689 No free full text.

Abstract: PURPOSE OF REVIEW: The host immune system is arguably involved in nearly every step of hepatitis C virus (HCV) infection. In patients, the outcome, whether it is a natural infection or results from an interferon-alpha-based treatment, is determined by a series of complex host-virus interactions. In this review, we focus on the state of research addressing the immune mechanisms critical for viral clearance and disease resolution. Additional discussion is devoted to the evasion and blockade tactics of HCV as well as to current efforts aimed at disrupting the replication cycle of this well-evolved virus. Current theories of immune-mediated injury of hepatocytes are also discussed. RECENT FINDINGS: Strong and persistent CD8 and CD4 T-cell responses are critical in HCV clearance. Although each may play a unique role in the process, the intrahepatic interferon (IFN)-gamma produced by these cells is central to their antiviral action. IFN-alpha/beta alone, without triggering subsequent HCV-specific T-cell responses, may not lead to a sustained viral response in vivo. Synergism among several immune cells, including T, NK, and NKT cells is important for disease resolution. Additional data raise the possibility that viral clearance and liver injury are mediated through different effector mechanisms of T cells. HCV employs evasion and sabotage tactics to escape from the host's immune system. HCV NS3/4A serine protease can block viral activation of a key transcription factor in initiating cellular IFN response. A newly identified NS3 protease inhibitor can result in a reduction of viremia, illustrating the potential of the viral-enzyme-targeted drug in patients. SUMMARY: Current data provide a rationale to further explore immune augmentation as a therapeutic intervention in HCV infection.

Prince AM, Pawlotsky JM, Soulier A, Tobler L, Brotman B, Pfahler W, Lee DH, Li L, Shata MT. · Laboratory of Virology, The Lindsley F. Kimball Research Institute of the New York Blood Center, New York, NY 10021, USA. · J Viral Hepat. · Pubmed #15117325 No free full text.

Abstract: The availability of molecular beacon-based, real time polymerase chain reaction (PCR) and a semi-automated sample extraction procedure have made it possible for us to retrospectively examine HCV replication kinetics in HCV naive chimpanzees infected during the past 20 years. We compared these in 17 animals that developed chronic infection, and in 21 that developed self-limited infection. No differences were found in infecting dose, or replication kinetics in the acute phase between these two types of infection. An unanticipated finding was the fact that 10 of 17 animals developing chronic infection partially controlled virus replication for 48 +/- 48 weeks after typical acute phase viraemia, and prior to development of chronic infection. Twenty-nine out of 30 (29/30) sera, which were negative by quantitative PCR during the downregulated period, were, however, positive by the more sensitive Genprobe isothermal transcription-mediated amplification (TMA) assay. Thus, downregulation was not complete. Ten animals showing self-limited infection showed complete resolution of viraemia by TMA assay. Quasispecies analysis revealed that in all, except one case, the virus reappearing after downregulation was essentially identical to that of the originally infecting virus.

Talal AH, Shata MT, Markatou M, Dorante G, Chadburn A, Koch R, Neumann AU, Ribeiro RM, Perelson AS. · Department of Medicine, Weill Medical College of Cornell University, New York City, NY, USA. · J Acquir Immune Defic Syndr. · Pubmed #14722440 No free full text.

Abstract: Mathematical modeling of the biological effect of interferon on virus decay permits the quantification of the efficacy (epsilon) of blocking virion production in different patient populations. The viral dynamic and immunologic responses of hepatitis C virus (HCV) infection to daily interferon therapy were characterized in twelve patients co-infected with human immunodeficiency virus (HIV). Three out of the twelve patients (25%) achieved an early viral response, a two-log reduction in HCV RNA by week 12. The mean epsilon of IFN-alpha in blocking HCV and HIV production were 72% and 74%, respectively. For HCV epsilon was highest (97%) in the one patient who had a sustained viral response, while it was reduced in the other two patients (68% and 77%). Baseline HCV RNA and the number of CD3+CD56+16+ cells were inversely related (r = -0.89, p = 0.03), and baseline HCV-specific immune responses were significantly higher in the three patients with 2-log viral load reductions. These data suggest that: 1) interferon efficacy at blocking virion production is correlated with treatment outcome in HIV/HCV co-infected patients, 2) that immunodeficient patients can respond to standard IFN-alpha, 3) that both innate and adaptive immune responses may be important determinants of HCV RNA decline in response to interferon.

Shata MT, Tricoche N, Perkus M, Tom D, Brotman B, McCormack P, Pfahler W, Lee DH, Tobler LH, Busch M, Prince AM. · New York Blood Center, New York, NY 10021, USA. · Virology. · Pubmed #14554088 No free full text.

Abstract: In hepatitis C virus (HCV) infection, there is accumulating data suggesting the presence of cellular immune responses to HCV in exposed but seemingly uninfected populations. Some studies have suggested cross-reactive antigens rather than prior HCV exposure as the main reason for the immune responses. In this study we address this question by analyzing the immune response of chimpanzees that have been sequentially exposed to increasing doses of HCV virions. The level of viremia, as well as the immune responses to HCV at different times after virus inoculation, were examined. Our data indicate that HCV infective doses as low as 1-10 RNA (+) virions induce detectable cellular immune responses in chimpanzees without consistently detectable viremia or persistent seroconversion. However, increasing the infective doses of HCV to 100 RNA (+) virions overcame the low-inoculum-induced immune response and produced high-level viremia followed by seroconversion.

Shata MT, Anthony DD, Carlson NL, Andrus L, Brotman B, Tricoche N, McCormack P, Prince A. · New York Blood Center, Lindsley F. Kimball Research Institute, Virology Laboratory, New York 10021, USA. · J Viral Hepat. · Pubmed #12431201 No free full text.

Abstract: The immune response to hepatitis C virus (HCV) is believed to be critical in determining the outcome of the disease. In this study we have analysed epitope recognition, cytokine profile, and anti-HCV antibody responses in chronically HCV-infected and recovered chimpanzees. Quantitative measurement of anti-HCV antibody in HCV-infected chimpanzees revealed that the response in HCV- recovered chimpanzees peaked within 4-20 weeks. In contrast, the anti-HCV antibody responses in chronically HCV infected chimpanzees did not peak until 100-200 weeks after infection, and decreased gradually thereafter. T cell proliferation assays measuring responses to pooled HCV proteins revealed significant increases in the 3H-uptake during the early stages of infection in recovered chimpanzees in comparison to the chronically infected ones. Class I-restricted epitopes of the core, and NS3 proteins of HCV were analysed using 9-10 mer overlapping peptides covering the core and NS3 proteins, and IFN-gamma ELISPOT technique. Our data indicated early and broad class-I restricted core, and NS3 protein epitope recognitions in HCV-recovered chimpanzees but not in chimpanzees that had been chronically infected. Additionally, dominant epitopes recognized early in infection (8 weeks) were no longer recognized later in infection (followed up to 64 weeks). Cytokines profiling revealed a 50-fold increase in TNF-alpha secretion in the supernatant of core-specific CD8 memory cells of the chronically infected chimpanzees in comparison to the recovered ones. In summary, multiple parameters correlate with HCV recovery in chimpanzees.

Yao ZQ, Shata MT, Tricoche N, Shan MM, Brotman B, Pfahler W, Hahn YS, Prince AM. · Department of Microbiology and Pathology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA. · Virology. · Pubmed #16368125 No free full text.

Abstract: Chimpanzee is a unique animal model for HCV infection, in which about 50% of infections resolve spontaneously. It has been reported that the magnitude of T cell responses to HCV core in recovered chimpanzees is greater than that in chronically infected ones. However, the mechanism(s) by which the chimpanzees with resolved infection overcome core-mediated immunosuppression remains unknown. In this study, we examined the effect of HCV core on T cell responsiveness in chimpanzees with resolved and chronic HCV infection. We found that core protein strongly inhibited T cell activation and proliferation in chimpanzees with chronic infection, while this inhibition was limited in chimpanzees with resolved infection. Notably, the level of gC1qR, as well as the binding of core protein, on the surface of T cells was lower in recovered chimpanzees when compared to chimpanzees with chronic HCV infection. Intriguingly, the observed differences in gC1qR expression levels and susceptibility to core-induced suppression amongst HCV-chronically infected and recovered chimpanzees were observed prior to HCV challenge, suggesting a possible genetic determination of the outcome of infection. These findings suggest that gC1qR expression on the surface of T cells is crucial for HCV core-mediated T cell suppression and viral clearance, and that represents a novel mechanism by which a virus usurps host machinery for persistence.