Diverged Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen-Restricted Immune Pressure

Many hepatitis C virus (HCV) infections worldwide are with the genotype I and 3 strains of the virus. Cellular immune responses are known to be important in the containment of HCV genotype I 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 HI-A-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 la and 136 individuals with genotype 3a infection. We identified 51 HILA-associated viral polymorphisms (32 for genotype la and 19 for genotype 3a). Of these putative viral adaptation sites, six fell within previously published epitopes. Only two HI-A-associated viral polymorphisms were common to both genotypes. In the remaining sites with HI-A-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 HI-A-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. (HEPATOLOGY 2009;50:1017-1029.)