Divergent adaptation of Hepatitis C virus genotypes to HLA-restricted immune pressure: relevance to HCV infection and vaccine design
Gaudieri, S., Rauch, A., James, I., Pfafferott, K., Cheng, W., McCaughan, G., Jeffrey, G., Mollison, L., Furrer, H., Günthard, H., Hirschel, B., Klenerman, P., Mallal, S., Nolan, D., John, M. and Lucas, M. (2009) Divergent adaptation of Hepatitis C virus genotypes to HLA-restricted immune pressure: relevance to HCV infection and vaccine design. In: 16th International Symposium on Hepatitis C Virus & Related Viruses, 3 - 7 October 2009, Nice, France.
The Hepatitis C virus (HCV) genotypes 1 and 3 account for a large number of infections worldwide but cross-protection between these two genotypes is limited. 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 leucocyte antigens (HLAs) have been identified. In contrast, there is almost no information known about the equivalent responses to genotype 3. Immune escape mechanisms utilized by HCV include the evolution of viral polymorphisms (‘adaptations’) that abrogate this host-viral interaction. 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 across the non-structural proteins of HCV. We identified 51 HLA-associated viral polymorphisms (32 for genotype 1a and 19 for genotype 3a). Of these putative viral adaptation sites, only two 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. Conclusion: There is limited overlap in HLA-associated polymorphisms in the non-structural 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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|Murdoch Affiliation:||Institute for Immunology and Infectious Diseases|
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