CD8 Epitope Escape and Reversion in Acute HCV Infection

Timm, Joerg; Lauer, Georg M.; Kavanagh, Daniel G.; Sheridan, Isabelle; Kim, Arthur Y.; Lucas, Michaela; Pillay, Thillagavathie; Ouchi, Kei; Reyor, Laura L.; Wiesch, Julian Schulze zur; Gandhi, Rajesh T.; Chung, Raymond T.; Bhardwaj, Nina; Klenerman, Paul; Walker, Bruce D.; Allen, Todd M.

doi:10.1084/jem.20041006

Cited by 296 publications

(338 citation statements)

References 54 publications

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“…HCV genotype was probably not a factor in the outcome of PD-1 blockade. The quality of T-cell immunity varies widely in humans and chimpanzees even when infection is established with viruses of the same genotype or subtype (7,13,14,(24)(25)(26)(27)(28)(29). It is therefore likely that successful PD-1 therapy in Ch5300 was due to priming and/or maintenance of a broad T-cell response that could be rescued regardless of HCV genotype.…”

Section: Resultsmentioning

confidence: 99%

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Fuller

Callendret

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

156

133

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Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.

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Section: Resultsmentioning

confidence: 99%

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Fuller

Callendret

Zhu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

156

133

View full text Add to dashboard Cite

show abstract

“…22 For example, Timm et al 73 recently observed a strong association between sequence variation within an immunodominant HLA-B*8 restricted NS3 epitope and expression of HLA-B*8, also supporting reproducible allele-specific selection pressures at the population level. Ray et al 74 performed a study in the well-documented Irish cohort and compared sequences present in serum obtained 18-22 years after infection to sequences present in the shared inoculum.…”

Section: Role Of Class I Alleles In Hcv Infectionmentioning

confidence: 94%

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection

Thimme

2007

Genes Immun

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The immunobiology of hepatitis C virus (HCV) is significantly influenced by the host immune response to the virus, especially by virus-specific T-cell responses. Virus-specific T cells are restricted by human leucocyte antigen class I and II molecules. Of note, associations between these polymorphic loci and outcome and course of HCV infection have been reported in large and well-documented cohorts. This review will briefly summarize these studies and focus especially on the immunological and virological basis for the reported associations. The outcome and course of HCV infection is most likely determined by a complex interplay of genetic, immunological and virological factors. A better understanding of these host-virus interactions is essential not only to gain better insights into the mechanisms of viral clearance and persistence but also for the development of new antiviral vaccine strategies.

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“…Carriage of the restricting HLA allele was associated with viral polymorphisms at several sites within immunogenic epitopes, consistent with viral escape from HLA-restricted immune pressure. At multiple sites, including experimentally established viral escape sites (for example, NS3-1397-1398 for HLA-B*0801 and NS5B-2841 and 2846 for HLA-B*2705 20,[23][24][25], there was nearly complete conservation in the alternative genotype, even in individuals carrying the relevant HLA alleles (Fig. 2).…”

Section: Amino Acid Variation Within Published and Predicted Viral Epmentioning

confidence: 99%

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

et al. 2009

Self Cite

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Many hepatitis C virus (HCV) infections worldwide are with the genotype 1 and 3 strains of the virus. Cellular immune responses are known to be important in the containment of HCV genotype 1 infection, and many genotype 1 T cell targets (epitopes) that are presented by host human leukocyte antigens (HLAs) have been identified. In contrast, there is almost no information known about the equivalent responses to genotype 3. Immune escape mechanisms used by HCV include the evolution of viral polymorphisms (adaptations) that abrogate this host-viral interaction. Evidence of HCV adaptation to HLA-restricted immune pressure on HCV can be observed at the population level as viral polymorphisms associated with specific HLA types. To evaluate the escape patterns of HCV genotypes 1 and 3, we assessed the associations between viral polymorphisms and specific HLA types from 187 individuals with genotype 1a and 136 individuals with genotype 3a infection. We identified 51 HLA-associated viral polymorphisms (32 for genotype 1a and 19 for genotype 3a). Of these putative viral adaptation sites, six fell within previously published epitopes. Only two HLA-associated viral polymorphisms were common to both genotypes. In the remaining sites with HLA-associated polymorphisms, there was either complete conservation or no significant HLA association with viral polymorphism in the alternative genotype. This study also highlights the diverse mechanisms by which viral evasion of immune responses may be achieved and the role of genotype variation in these processes. Conclusion: There is little overlap in HLA-associated polymorphisms in the nonstructural proteins of HCV for the two genotypes, implying differences in the cellular immune pressures acting on these viruses and different escape profiles. These findings have implications for future therapeutic strategies to combat HCV infection, including vaccine design.

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CD8 Epitope Escape and Reversion in Acute HCV Infection

Cited by 296 publications

References 54 publications

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1)

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

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