Immunologic evidence for lack of heterologous protection following resolution of HCV infection

Abstract

Chronic HCV infection is typically characterized by a lack of virus-specific CD4+ T-cell proliferative responses, but strong responses have been described in a subset of persons with persistent uncontrolled viremia. One possible explanation for these responses is that they were primed by an earlier resolved infection and do not recognize the current circulating virus. To address this, we defined the targeted epitopes in persons chronically infected with different HCV genotypes (GT), and sequenced the autologous virus present in vivo. HCV-specific CD4+ T cell lines of 44 subjects (24 subjects with current GT1 infection / 20 subjects with current non-GT1 infection) were tested with a set of overlapping GT1a peptides covering the entire HCV-polyprotein and responses were mapped to single immunogenic peptides. Overall, more GT1-specific CD4+ T cell responses were detected in subjects with chronic non-GT1 infection compared to subjects with chronic GT1 infection (p=0.017), despite a closer match of the peptides to GT1 viruses. We found serological evidence of a previous exposure to GT1 in four subjects with non-GT1 infection, and these persons also demonstrated significantly more responses than non-GT1 subjects in whom genotype and HCV serotype were identical (p=0.0003). Comparison of recognition of GT1-specific peptides to peptides representing autologous virus revealed the absence of cross-recognition of the autologous circulating virus, supporting the hypothesis that these responses represent an “immunological T cell scar“ from previous exposure to GT1 virus that had been cleared. These data suggest that persisent HCV infection can occur in the presence of an HCV-specific T-cell response that was primed by a heterologous HCV strain, and that clearance of one GT does not protect against subsequent exposure to a second GT. Furthermore, they suggest that persistent viremia per se is not immunosuppressive for HCV-specific CD4+ T cells, but rather that chronic viremia leads to selective elimination of adaptive CD4+ T cell responses to the epitopes presented in vivo.