Escape from HLA-B*08-Restricted CD8 T Cells by Hepatitis C Virus Is Associated with Fitness Costs

Abstract

The inherent sequence diversity of the hepatitis C virus (HCV) represents a major hurdle for the adaptive immune system to control viral replication. Mutational escape within targeted CD8 epitopes during acute HCV infection has been well documented and is one possible mechanism for T-cell failure. HLA-B*08 was recently identified as one HLA class I allele associated with spontaneous clearance of HCV replication. Selection of escape mutations in the immunodominant HLA-B*08-restricted epitope HSKKKCDEL 1395-1403 was observed during acute infection. However, little is known about the impact of escape mutations in this epitope on viral replication capacity. Their previously reported reversion back toward the consensus residue in patients who do not possess the B*08 allele suggests that the consensus sequence in this epitope is advantageous for viral replication in the absence of immune pressure. The aim of this study was to determine the impact of mutational escape from this immunodominant epitope on viral replication. We analyzed it with a patient cohort with chronic HCV genotype 1b infection and in a single-source outbreak (genotype 1b). Sequence changes in this highly conserved region are rare and selected almost exclusively in the presence of the HLA-B*08 allele. When tested in the subgenomic replicon (Con1), the observed mutations reduce viral replication compared with the prototype sequence. The results provide direct evidence that escape mutations in this epitope are associated with fitness costs and that the antiviral effect of HLA-B*08-restricted T cells is sufficiently strong to force the virus to adopt a relatively unfavorable sequence.

Divergent Adaptation of Hepatitis C Virus Genotypes 1 and 3 to Human Leukocyte Antigen–Restricted Immune Pressure†

“…Carriage of the restricting HLA allele was associated with viral polymorphisms at several sites within immunogenic epitopes, consistent with viral escape from HLA-restricted immune pressure. At multiple sites, including experimentally established viral escape sites (for example, NS3-1397-1398 for HLA-B*0801 and NS5B-2841 and 2846 for HLA-B*2705 20,[23][24][25], there was nearly complete conservation in the alternative genotype, even in individuals carrying the relevant HLA alleles (Fig. 2).…”

Does a relationship of HLA B alleles with course of hepatitis C virus infection in children and youth and efficacy of its treatment exist?

“…Za wpływające na przebieg zakażenia uważa się m.in. cechy genetyczne pacjenta, szczególnie układ genów dla antygenów zgodności tkankowej -główny układ zgodności tkankowej (major histocompatibility complex -MHC), ludzkie antygeny leukocytarne (human leucocyte antigens -HLA) [1][2][3][4][5][6][7]. Skuteczność podejmowanej terapii także być może ma związek z układem genów dla HLA [8][9][10].…”

“…Wśród czynników, które prawdopodobnie wpływają na opisywane korelacje alleli HLA B z przebiegiem zakażenia HCV czy też z efektywnością stosowanej terapii przeciwwirusowej, wymienia się: obszar geograficzny, z którego wywodzą się pacjenci (odmienny skład rasowy różnych społeczeństw i różne determinanty genetyczne u osób różnych ras, odmienność występujących w różnych rejonach świata odmian genetycznych wirusa), w mniej szym stopniu płeć czy wiek pacjentów [3,9,17]. Za czynnik wpływający najsilniej na wyniki badań dotyczących zależności między układem HLA gospodarza a przebiegiem zakażenia HCV uważa się genotyp wirusa [2,3,11].…”

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).…”