Effect of immune pressure on hepatitis C virus evolution: Insights from a single-source outbreak

Abstract

The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)–specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. Conclusion: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts. (Hepatology 2011;53:396-405)

Escape from a Dominant HLA-B*15-Restricted CD8 + T Cell Response against Hepatitis C Virus Requires Compensatory Mutations outside the Epitope

“…Alleles such as HLA-A*03, HLA-B*27, and HLA-B*57 have been described to be associated with spontaneous resolution of HCV infection (21,27,49). It has been highlighted that these "protective" HLA class I alleles highly reproducibly select for escape mutations in the corresponding immunodominant epitopes (21,29,33). A study of the mechanisms of protection by HLA-B*27 pointed out that a rather complex pattern of 2, or sometimes even 3, substitutions is selected (8).…”

“…Some of these escape mutations in viral epitopes are highly reproducible in patients sharing the same HLA class I alleles, suggesting reproducible selection pressure. At the population level, these reproducible escape mutations are visible as "footprints" of the corresponding HLA allele in the viral genomes of circulating isolates (12,29,39,41,51).…”

Linking Pig-Tailed Macaque Major Histocompatibility Complex Class I Haplotypes and Cytotoxic T Lymphocyte Escape Mutations in Simian Immunodeficiency Virus Infection

“…Compensatory mutations can become fixed in viral sequences, since returning to the wild type requires multiple simultaneous changes (7). Although studies of HIV polymorphisms in humans have been illuminating and have led to the successful identification of important CTL epitopes (8)(9)(10), the infecting virus strain and timing of infection are not always known in humans, and this lack of knowledge complicates analyses. Simian immunodeficiency virus (SIV) infection of pig-tailed macaques (Macaca nemestrina) is a very useful model for the study of HIV pathogenesis.…”

“…Incisive human studies have linked HIV-1 mutations with particular human leukocyte antigen (HLA) class I alleles, revealing important clues to CTL immunity, epitope discovery, and the control and evolution of HIV (8,9,(23)(24)(25). Several studies have also linked hepatitis C virus (HCV) immune system-driven adaptations to HLA class I alleles, and elegant studies have estimated the false discovery rates of such linkage analyses (10,(26)(27)(28). Linking CTL escape mutations with pig-tailed macaque MHC-I haplotypes both will improve this animal model and could in turn facilitate the design of efficacious CTL vaccines that limit CTL escape.…”

Genetic Variation of Host Immune Response Genes and Their Effect on Hepatitis C Infection and Treatment Outcome

“…However, the relationship between HLA and HCV outcome should be considered in the context of viral variation. It is likely that viral immune escape mutations present in the incoming virus will affect HCV infection outcome as has been shown using single source outbreak cohorts (Merani, Petrovic et al 2011) (Salloum, Oniangue-Ndza et al 2008). Accordingly, viral adaptation to the host's HLA-restricted immune response will be an important correlate of infection outcome (Figure 1).…”