Protection by HLA-B27 in HCV infection: role of virological and immunological factors

Abstract

B27 is a highly protective HLA allele in HCV infection. Indeed, 80% of B27+ Irish women with accidental HCV genotype 1b infection resolved the infection spontaneously while only 20% developed chronic infection (McKiernan et al., Hepatology 2004). We recently linked this protective effect of HLA-B27 as well as viral evolution within the few B27+ individuals who developed chronic infection to a single, immunodominant HLA-B27 restricted CD8+ T cell epitope within NS5B (Neumann-Haefelin et al., Hepatology 2006). In order to further define the mechanisms of protection mediated by this epitope, we analyzed the virological and immunological characteristics in more detail. To determine the replication capacity of the variants observed in vivo, we cloned these into a subgenomic Con1 replicon harbouring a luciferase reporter gene. All variants were still able to replicate, however a significant reduction in viral replication was observed for most mutants indicating impaired fitness. Interestingly, some clustered mutations seem to represent compensatory rather than escape mutations that restore viral fitness partially. The epitope has an enormous binding affinity to HLA-B27 molecules and cross-reacts with peptides from clinically common microorganisms, indicating that heterologous immunity contributes to the dominant effect of this epitope. In conclusion, our results show that both, immunological factors (high binding affinity, cross-reactivity) as well as virological factors (high viral fitness cost) contribute to the protective effect of HLA-B27 observed in vivo. We hypothesize that viral escape within this epitope is constrained, giving the strong CD8+ T cell response enough time to clear the virus in most acutely infected patients before viral evolution can lead to the establishment of persistent infection.