Broad Repertoire of the CD4+ Th Cell Response in Spontaneously Controlled Hepatitis C Virus Infection Includes Dominant and Highly Promiscuous Epitopes

Abstract

A vigorous hepatitis C virus (HCV)-specific Th cell response is regarded as essential to the immunological control of HCV viremia. The aim of this study was to comprehensively define the breadth and specificity of dominant HCV-specific CD4(+) T cell epitopes in large cohorts of subjects with chronic and spontaneously resolved HCV viremia. Following in vitro stimulation of PBMC, HCV-specific cell cultures from each subject were screened with an overlapping panel of synthetic 20-mer peptides spanning the entire HCV polyprotein. Of 22 subjects who spontaneously controlled HCV viremia, all recognized at least one of a group of six epitopes situated within the nonstructural (NS) proteins NS3, NS4, and NS5, each of which was detected by >30% of subjects, but most subjects recognized additional, more heterogeneous specificities. In contrast, none of the most frequently targeted epitopes was detected by >5% of persons with chronic infection. The most frequently recognized peptides showed promiscuous binding to multiple HLA-DR molecules in in vitro binding assays and were restricted by different HLA-DR molecules in functional assays in different persons. These data demonstrate that predominant CD4(+) T cell epitopes in persons with resolved HCV infection are preferentially located in the nonstructural proteins and are immunogenic in the context of multiple class II molecules. This comprehensive characterization of CD4(+) T cell epitopes in resolved HCV infection provides important information to facilitate studies of immunopathogenesis and HCV vaccine design and evaluation.

HCV‐specific T‐cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance

“…However, other studies using similar techniques failed to support this finding and showed that CD4+ T-cells responses were broad, but not specifically targeting only NS proteins [35]. In that light the Core protein-responses detected prior to seroconversion in subsequently resolving individuals is of interest as Core protein-responses are more abundant before onset of infection and shift to dominant NS-responses over seroconversion.…”

Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

“…[1][2][3][4][5][6][7][8][9] In contrast, chronic infection is characterized by less vigorous and narrowly focused CD4 and CD8 T cell responses. The mechanisms responsible for immune failure in patients who do not succeed in clearing the virus spontaneously are still unclear.…”

“…Most recent reports used wide panels of 10-to 15-mer HCV peptides that cannot distinguish the relative contribution of CD4 and CD8 cells to the overall antiviral T cell response. [5][6][7][8][9][10][11] Alternatively, a small number of preselected epitopes of known HLA restriction or whole recombinant HCV proteins were tested. [12][13][14][15][16][17][18] Moreover, only limited information is available about the ex vivo profile of cytokine production in the acute phase of infection, because ELISPOT and intracellular cytokine staining (ICS) analysis were based on the measure of interferon-␥ (IFN-␥) only.…”

“…To address this issue, we analyzed the breadth, vigor, and quality of CD4 and CD8 responses simultaneously with panels of peptides covering the entire HCV sequence or containing the HLA-A2-binding motif, and with recombinant HCV proteins in 16 patients with acute HCV infection by tetramer staining, ELISPOT, and intracellular cytokine staining for interferon ␥, interleukin ( S pontaneous clearance of hepatitis C virus infection occurs in a small percentage of acutely infected patients and is associated with a vigorous cellular immune response of a broad specificity. [1][2][3][4][5][6][7][8][9] In contrast, chronic infection is characterized by less vigorous and narrowly focused CD4 and CD8 T cell responses. The mechanisms responsible for immune failure in patients who do not succeed in clearing the virus spontaneously are still unclear.…”

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection

“…Most studies found that in acute resolving HCV infection, CD4 þ Tcell responses target mainly non-structural proteins, whereas in persistent HCV infection, CD4 þ T-cell responses to the core protein dominate. 5,9,[92][93][94] The chimpanzee model of HCV allowed a more direct demonstration of the effect of CD4 þ T cells: the antibody-mediated depletion of CD4 þ cells resulted in a prolonged viraemia, the emergence of viral quasispecies containing escape mutations within targeted CD8 þ T-cell epitopes, and finally viral persistence. 18 As CD4 þ T-cell responses are restricted by HLA class II molecules (Figure 1), it has been postulated that, similar to HLA class I alleles, certain HLA class II alleles might be associated with different outcomes of HCV infection.…”