High Prevalence of Hypervariable Region 1-Specific and -Cross-Reactive CD4+ T Cells in HCV-Infected Individuals Responsive to IFN-α Treatment

Abstract

The hypervariable region 1 (HVR1) of the putative envelope 2 protein of the hepatitis C virus (HCV) is the most variable part of the whole HCV polyprotein. Anti-HVR1 antibodies have been shown to protect against HCV infection, indicating that this region contains an important neutralization determinant. Recently we and others have demonstrated that HVR1 is also a T cell determinant able to activate helper T cell responses during HCV infection. In order to investigate the role of the immune response against HVR1 during HCV infection we have evaluated the humoral and lymphoproliferative responses to a panel of HVR1 peptides in HCV-infected patients with different outcomes of the disease following interferon-alpha (IFN-alpha) treatment. We observed that the frequency of anti-HVR1 T cell responses was significantly higher in patients who recovered after IFN-alpha therapy than in those who did not, while no differences in the anti-HVR1 antibody reactivities were detected. In addition, by generating HVR1-specific T cell lines and clones we identified human leukocyte-associated antigens DR4 restricted T cell epitopes in the carboxy-terminus of HVR1 and we demonstrated that broadly cross-reactive HVR1 T cells are elicited by HVR1.

Genetic Immunization of Wild-Type and Hepatitis C Virus Transgenic Mice Reveals a Hierarchy of Cellular Immune Response and Tolerance Induction against Hepatitis C Virus Structural Proteins

“…These authors postulated that this might be a mechanism for viral escape and persistence. Recent publications have shown that active cellular immune responses against the E2 are frequently present in persons infected with HCV (8,38). A similar observation can be inferred from a study of cell-mediated immunity during acute infection of chimpanzees, in which several CTL epitopes were identified in the E2 but not in the core region and the strength of CTL responses against these epitopes was associated with viral clearance (7).…”

Changes in hypervariable region 1 of the envelope 2 glycoprotein of hepatitis C virus in children and adults with humoral immune defects

“…However, cellular immune responses may also play a role in the selection of viral variants [Eckels et al, 2000]. Indeed, it is now known that viral clearance is associated with persistently strong and broad T-cell responses [Del Porto et al, 2000;Lechner et al, 2000]. Rapid and serial changes in HVR-1 have been demonstrated in the acute phase of HCV infection as well [Sakamoto et al, 1994].…”

Localization of CD4+T cell epitope hotspots to exposed strands of HIV envelope glycoprotein suggests structural influences on antigen processing

“…There is some evidence from other experimental systems that the same peptides are recognized by both Ig molecules and the TCRs of CD4 ϩ T cells (46,47). Two recent studies of human hepatitis C virus have mapped both Ig binding and T h epitopes to the hypervariable region of the env protein (48,49). In support of this theory, antibodies and CD4 ϩ T cells have been shown to recognize epitopes on the HIV env V2, V3, and V4 loops.…”