Genetic variability of hepatitis C virus non‐structural protein 3 and virus‐specific CD8+ response in patients with chronic hepatitis C

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Abstract
Hepatitis C virus (HCV) variation in specific T‐cell epitopes may represent a mechanism of viral persistence in chronic infection. We examined the HCV non‐structural protein 3 (NS3), including the immunologically relevant epitopes HCV NS3‐2 KLVALGINAV (human leukocyte antigen [HLA]‐A2‐restricted) and HCV NS3‐1391 LIFCHSKKK (HLA‐A3‐restricted), in 22 HLA‐A2+ patients with chronic infection. Significant amino acid variation was found in HCV NS3‐2 epitope sequences when compared to the HCV‐1 prototype virus. Six of the nine different HCV NS3‐2 peptide variants were identified in patients with HCV NS3‐2‐specific CD8+ cells, detected with an HLA‐A2 tetramer made with the HCV‐1 prototype peptide. Phylogenetic analysis, including HCV reference sequences other than HCV‐1, suggested however that most of the variations in the HCV NS3‐2 epitope could be related to genetic heterogeneity between HCV reference subtypes. Variation was less common when comparing HCV NS3‐2 epitope sequences from the clinical isolates to the most‐closely related HCV reference subtype in each case. Some subtype‐independent variations were found in epitopic residues probably important for T‐cell receptor interaction. In contrast, no significant variation was found in HLA primary anchor sites, flanking regions, or in the contiguous HLA A3‐restricted CD8+ T‐cell epitope. Ongoing variation was not evident in two selected patients with follow‐up. In conclusion, (i) the HCV NS3‐2 epitope is not conserved between different HCV strains/subtypes, and (ii) an HLA‐A2 tetramer loaded with the HCV‐1 prototype NS3‐2 peptide may still detect NS3‐specific CD8+ cells in some patients with variant viruses. These data may be useful to improve T‐cell assays using HCV NS3 peptides, taking into account the genetic diversity of this virus. J. Med. Virol. 72:575–585, 2004.