Constrained pattern of viral evolution in acute and early HCV infection limits viral plasticity

Abstract

Cellular immune responses during acute Hepatitis C virus (HCV) and HIV infection are a known correlate of infection outcome. Viral adaptation to these responses via mutation(s) within CD8+ T-cell epitopes allows these viruses to subvert host immune control. This study examined HCV evolution in 21 HCV genotype 1-infected subjects to characterise the level of viral adaptation during acute and early HCV infection. Of the total mutations observed 25% were within described CD8+ T-cell epitopes or at viral adaptation sites. Most mutations were maintained into the chronic phase of HCV infection (75%). The lack of reversion of adaptations and high proportion of silent substitutions suggests that HCV has structural and functional limitations that constrain evolution. These results were compared to the pattern of viral evolution observed in 98 subjects during a similar phase in HIV infection from a previous study. In contrast to HCV, evolution during acute HIV infection is marked by high levels of amino acid change relative to silent substitutions, including a higher proportion of adaptations, likely reflecting strong and continued CD8+ T-cell pressure combined with greater plasticity of the virus. Understanding viral escape dynamics for these two viruses is important for effective T cell vaccine design.

Figure 1. Existing sequence variations within CD8⁺ T-cell epitopes.

Number of existing variations at first sampling time-point within CD8⁺ T-cell epitopes for matching HLA types and non-matching HLA types (relative to “wildtype” = HCV reference) and reversions in absence of specific HLA-restricted immune pressure.

Figure 2. HCV sequences in different subjects for the HLA-B*27 epitope in NS5B.

Single asterick indicates site of HLA-association based on 2-digit HLA typing and double asterick based on 4-digit HLA typing. Dots indicate identity to consensus. Numbering indicates position with the NS5B protein. Black indicates subject with HLA-B*27. Dark grey box indicates time-points after cessation of therapy.

Figure 3. Plot of synonymous and non-synonymous changes during acute and early infection for HCV (A and B) and HIV (C and D).

Representative subjects are shown that had similar sampling time-points. Time-points for HIV subjects were determined by adding 4 weeks to first time-points to represent time since infection.