Cellular immune responses in seronegative sexual contacts of acute hepatitis C patients

Abstract

Acute hepatitis C virus (HCV) is typically defined as new viremia and antibody seroconversion. Rates and immunologic correlates of hepatitis C clearance have therefore been based on clearance of viremia only in individuals who initially had an antibody response. We sought to characterize the immunological correlates of clearance in patients with acute hepatitis C and their sexual contacts. We prospectively determined CD4(+) and CD8(+) cytotoxic T-lymphocyte responses in index patients with acute HCV and their sexual contacts who developed acute infection, either with or without spontaneous clearance, as well as those contacts who never developed viremia. Responses were measured using proliferation and ELISpot assays for CD4(+) and CD8(+) responses. We demonstrate in this prospective study that cellular immune responses can develop in exposed but persistently aviremic and antibody-negative individuals as well as those individuals with spontaneous clearance of acute HCV. These findings lend further credence to the importance of cellular immune responses in recovery from HCV and suggest that low exposure to HCV may lead to development of HCV-specific immune responses without ongoing HCV replication. This finding has important implications for HCV vaccine and therapeutic development.

FIG. 1.

Time course of ALT, HCV RNA, and immune responses. Serum ALT, HCV RNA,CD4⁺ proliferative response, and IFN-γ in subjects with spontaneous recovery (A), contacts with persistent aviremia but detectable HCV-specific immune responses (B), contacts with chronic evolution (C), and noninfected contacts with no HCV (D). The upper two rows show the ALT (40 U/liter; filled circles) and mean serum HCV RNA levels (filled diamonds). The third row shows CD4⁺ proliferative T-cell responses to four HCV proteins (core, NS3, NS4, and NS5) expressed as SI (y axis). The cutoff for a positive response is an SI of 3. Bars represent mean responses to a given antigen, and lines represent SDs. The lower row shows numbers of SFCs expressing IFN-γ in the ELISpot assay after stimulation with core protein, NS3, NS4, and NS5. Bars represent mean responses, and lines represent SDs. Horizontal lines represent cutoff values.

FIG. 2.

HCV-specific CD4⁺ proliferative responses in patients and contacts. HCV-specific CD4⁺ T-cell proliferative response in subjects with spontaneous recovery (filled circles), persistent aviremia (open circles), and chronic evolution (filled diamonds) are shown. Responses at week 12 (A) and the end of follow-up (B) are shown. Each point represents a subject. Each horizontal line represents the cutoff for a given response. The lower left panel represents the response to tetanus toxoid at baseline.

FIG. 3.

HCV-specific CTL activity from HLA-A2-positive HCV patients stimulated with peptide pools, including the following: subjects with spontaneous recovery, contacts with persistent aviremia but detectable immune responses, subjects with chronic evolution, and noninfected subjects with no detectable HCV-specific immune responses. At the baseline (A) no CTL responses were detected in any index patients or contacts. At week 12 (B) and at the end of follow-up (C) HCV-specific CTL responses are more vigorous in subjects with spontaneous recovery and persistent aviremia than in those with evolution to chronic disease. Each bar represents the mean response to a given peptide pool. The details of the peptide pools are given in Materials and Methods. The vertical line represents the cutoff for each response.