Absence of viral escape within a frequently recognized HLA-A26-restricted CD8+ T-cell epitope targeting the functionally constrained hepatitis C virus NS5A/5B cleavage site

CD8+ T-cell responses are central for the resolution of hepatitis C virus (HCV) infection, and viral escape from these CD8+ T-cell responses has been suggested to play a major role in HCV persistence. However, the factors determining the emergence of CD8 escape mutations are not well understood. Here, the first identification of four HLA-A26-restricted CD8+ T-cell epitopes is reported. Of note, two of these four epitopes are located in the NS3/4A and NS5A/5B cleavage sites. The latter epitope is targeted in all (three of three) patients with acute, resolving HCV infection and in a relatively high proportion (four of 14) of patients with chronic HCV infection. Importantly, the epitope corresponding to the NS5A/5B cleavage site is characterized by the complete absence of sequence variations, despite the presence of functional virus-specific CD8+ T cells in our cohort. These results support previous findings that showed defined functional constraints within this region. They also suggest that the absence of viral escape may be determined by viral fitness cost and highlight an attractive target for immunotherapies.

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Hepatitis C virus - T-cell responses and viral escape mutations

European Journal of Immunology ◽

10.1002/eji.201141593 ◽

2011 ◽

Vol 42 (1) ◽

pp. 17-26 ◽

Cited By ~ 28

Author(s):

Danijela Petrovic ◽

Eugene Dempsey ◽

Derek G. Doherty ◽

Dermot Kelleher ◽

Aideen Long

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

T Cell Responses ◽

Viral Escape ◽

Cell Responses

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The Clearance of Hepatitis C Virus Infection in Chimpanzees May Not Necessarily Correlate with the Appearance of Acquired Immunity

Journal of Virology ◽

10.1128/jvi.77.2.862-870.2003 ◽

2003 ◽

Vol 77 (2) ◽

pp. 862-870 ◽

Cited By ~ 63

Author(s):

Michael Thomson ◽

Michelina Nascimbeni ◽

Michael B. Havert ◽

Marian Major ◽

Sophia Gonzales ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

T Cell Responses ◽

Distinct Pattern ◽

Hcv Infection ◽

Interleukin 4 ◽

Mrna Levels ◽

Cell Responses ◽

Ifn Γ

ABSTRACT Clearance of hepatitis C virus (HCV) infection in humans and chimpanzees is thought to be associated with the induction of strong T-cell responses. We studied four chimpanzees infected with HCV derived from an infectious full-length HCV genotype 1b cDNA. Two of the chimpanzees cleared the infection to undetectable levels for more than 12 months of follow-up; the other two became persistently infected. Detailed analyses of HCV-specific immune responses were performed during the courses of infection in these chimpanzees. Only weak and transient T helper responses were detected during the acute phase in all four chimpanzees. A comparison of the frequency of gamma interferon (IFN-γ)-producing CD4+ and CD8+ T cells in peripheral blood by ELISpot assay did not reveal any correlation between viral clearance and T-cell responses. In addition, analyses of IFN-γ, IFN-α, and interleukin-4 mRNA levels in liver biopsies, presumably indicative of intrahepatic T-cell responses, revealed no distinct pattern in these chimpanzees with respect to infection outcome. The present study suggests that the outcome of HCV infection in chimpanzees is not necessarily attributable to HCV sequence variation and that chimpanzees may recover from HCV infection by mechanisms other than the induction of readily detectable HCV-specific T-cell responses.

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Hepatitis C Virus (HCV)–Specific T Cell Responses in Injection Drug Users with Apparent Resistance to HCV Infection

The Journal of Infectious Diseases ◽

10.1086/593337 ◽

2008 ◽

Vol 198 (12) ◽

pp. 1749-1755 ◽

Cited By ~ 41

Author(s):

Prem H. Thurairajah ◽

Doha Hegazy ◽

Shilpa Chokshi ◽

Steve Shaw ◽

Andrew Demaine ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Injection Drug Users ◽

Drug Users ◽

T Cell Responses ◽

Hcv Infection ◽

Injection Drug ◽

Cell Responses ◽

Apparent Resistance

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Cellular immune selection with hepatitis C virus persistence in humans

Journal of Experimental Medicine ◽

10.1084/jem.20050121 ◽

2005 ◽

Vol 201 (11) ◽

pp. 1741-1752 ◽

Cited By ~ 210

Author(s):

Andrea L. Cox ◽

Timothy Mosbruger ◽

Qing Mao ◽

Zhi Liu ◽

Xiao-Hong Wang ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Sequence Evolution ◽

T Cell Epitopes ◽

Cell Responses ◽

Cellular Immune

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific cellular immune responses. To determine if immunologically driven sequence variation occurs with HCV persistence, we coordinately analyzed sequence evolution and CD8+ T cell responses to epitopes covering the entire HCV polyprotein in subjects who were followed prospectively from before infection to beyond the first year. There were no substitutions in T cell epitopes for a year after infection in a subject who cleared viremia. In contrast, in subjects with persistent viremia and detectable T cell responses, we observed substitutions in 69% of T cell epitopes, and every subject had a substitution in at least one epitope. In addition, amino acid substitutions occurred 13-fold more often within than outside T cell epitopes (P < 0.001, range 5–38). T lymphocyte recognition of 8 of 10 mutant peptides was markedly reduced compared with the initial sequence, indicating viral escape. Of 16 nonenvelope substitutions that occurred outside of known T cell epitopes, 8 represented conversion to consensus (P = 0.015). These findings reveal two distinct mechanisms of sequence evolution involved in HCV persistence: viral escape from CD8+ T cell responses and optimization of replicative capacity.

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Virus-specific T-cell responses associated with hepatitis C virus (HCV) persistence in the liver after apparent recovery from HCV infection

Journal of Medical Virology ◽

10.1002/jmv.20680 ◽

2006 ◽

Vol 78 (9) ◽

pp. 1190-1197 ◽

Cited By ~ 20

Author(s):

Juan A. Quiroga ◽

Silvia Llorente ◽

Inmaculada Castillo ◽

Elena Rodríguez-Iñigo ◽

Juan Manuel López-Alcorocho ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

T Cell Responses ◽

Hcv Infection ◽

Cell Responses

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Comprehensive Analysis of CD8+-T-Cell Responses against Hepatitis C Virus Reveals Multiple Unpredicted Specificities

Journal of Virology ◽

10.1128/jvi.76.12.6104-6113.2002 ◽

2002 ◽

Vol 76 (12) ◽

pp. 6104-6113 ◽

Cited By ~ 140

Author(s):

Georg M. Lauer ◽

Kei Ouchi ◽

Raymond T. Chung ◽

Tam N. Nguyen ◽

Cheryl L. Day ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Cell Response ◽

Critical Role ◽

T Cell Responses ◽

Comprehensive Analysis ◽

T Cell Response ◽

Hcv Infection ◽

Cell Responses

ABSTRACT The hepatitis C virus (HCV)-specific CD8+-T-cell response is thought to play a critical role in HCV infection. Studies of these responses have largely relied on the analysis of a small number of previously described or predicted HCV epitopes, mostly restricted by HLA A2. In order to determine the actual breadth and magnitude of CD8+-T-cell responses in the context of diverse HLA class I alleles, we performed a comprehensive analysis of responses to all expressed HCV proteins. By using a panel of 301 overlapping peptides, we analyzed peripheral blood mononuclear cells (PBMC) from a cohort of 14 anti-HCV-positive, HLA A2-positive individuals in an enzyme-linked immunospot assay. Only four subjects had detectable HLA A2-restricted responses in PBMC, and only 3 of 19 predicted A2 epitopes were targeted, all of which were confirmed by tetramer analysis. In contrast, 9 of 14 persons showed responses with more comprehensive analyses, with many responses directed against previously unreported epitopes. These results indicate that circulating HCV-specific CD8+-T-cell responses can be detected in PBMC in the majority of infected persons and that these responses are heterogeneous with no immunodominant epitopes consistently recognized. Since responses to epitopes restricted by single HLA alleles such as HLA A2 do not predict the overall response in an individual, more comprehensive approaches, as shown here, should facilitate definition of the role of the CD8+-T-cell response in HCV infection. Moreover, the low level or absence of responses to many predicted epitopes provides a rationale for immunotherapeutic interventions to broaden cytotoxic-T-lymphocyte recognition.

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Extracellular Hepatitis C Virus Core Protein Activates STAT3 in Human Monocytes/Macrophages/Dendritic Cells via an IL-6 Autocrine Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m110.217653 ◽

2011 ◽

Vol 286 (12) ◽

pp. 10847-10855 ◽

Cited By ~ 63

Author(s):

Robert S. Tacke ◽

Annie Tosello-Trampont ◽

Virginia Nguyen ◽

David W. Mullins ◽

Young S. Hahn

Keyword(s):

Dendritic Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Inflammatory Responses ◽

Critical Role ◽

T Cell Responses ◽

Hcv Infection ◽

Human Monocytes ◽

Cell Responses

Hepatitis C virus (HCV) infection is highly efficient in the establishment of persistent infection, which leads to the development of chronic liver disease and hepatocellular carcinoma. Impaired T cell responses with reduced IFN-γ production have been reported to be associated with persistent HCV infection. Extracellular HCV core is a viral factor known to cause HCV-induced T cell impairment via its suppressive effect on the activation and induction of pro-inflammatory responses by antigen-presenting cells (APCs). The activation of STAT proteins has been reported to regulate the inflammatory responses and differentiation of APCs. To further characterize the molecular basis for the regulation of APC function by extracellular HCV core, we examined the ability of extracellular HCV core to activate STAT family members (STAT1, -2, -3, -5, and -6). In this study, we report the activation of STAT3 on human monocytes, macrophages, and dendritic cells following treatment with extracellular HCV core as well as treatment with a gC1qR agonistic monoclonal antibody. Importantly, HCV core-induced STAT3 activation is dependent on the activation of the PI3K/Akt pathway. In addition, the production of multifunctional cytokine IL-6 is essential for HCV core-induced STAT3 activation. These results suggest that HCV core-induced STAT3 activation plays a critical role in the alteration of inflammatory responses by APCs, leading to impaired anti-viral T cell responses during HCV infection.

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Viral Sequence Evolution in Acute Hepatitis C Virus Infection

Journal of Virology ◽

10.1128/jvi.00995-07 ◽

2007 ◽

Vol 81 (21) ◽

pp. 11658-11668 ◽

Cited By ~ 73

Author(s):

Thomas Kuntzen ◽

Joerg Timm ◽

Andrew Berical ◽

Lia L. Lewis-Ximenez ◽

Andrea Jones ◽

...

Keyword(s):

T Cells ◽

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

Consensus Sequence ◽

T Cell Responses ◽

Hcv Infection ◽

Sequence Evolution ◽

Cell Responses ◽

Immunodeficiency Virus

ABSTRACT CD8+-T-cell responses play an important role in the containment and clearance of hepatitis C virus (HCV) infection, and an association between viral persistence and development of viral escape mutations has been postulated. While escape from CD8+-T-cell responses has been identified as a major driving force for the evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), a broader characterization of this relationship is needed in HCV infection. To determine the extent, kinetics, and driving forces of HCV sequence evolution, we sequenced the entire HCV genome longitudinally in four subjects monitored for up to 30 months after acute infection. For two subjects the transmission sources were also available. Of 53 total nonenvelope amino acid substitutions detected, a majority represented forward mutations away from the consensus sequence. In contrast to studies in HIV and SIV, however, only 11% of these were associated with detectable CD8+ T-cell responses. Interestingly, 19% of nonenvelope mutations represented changes toward the consensus sequence, suggesting reversion in the absence of immune pressure upon transmission. Notably, the rate of evolution of forward and reverse mutations correlated with the conservation of each residue, which is indicative of structural constraints influencing the kinetics of viral evolution. Finally, the rate of sequence evolution was observed to decline over the course of infection, possibly reflective of diminishing selection pressure by dysfunctional CD8+ T cells. Taken together, these data provide insight into the extent to which HCV is capable of evading early CD8+ T-cell responses and support the hypothesis that dysfunction of CD8+ T cells may be associated with failure to resolve HCV infections.

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