Tracking Virus-Specific CD4+T Cells during and after Acute Hepatitis C Virus Infection

• Type of Material: Article
• Authors: Michaela Lucas, University of Oxford; Axel Ulsenheimer, University of Munich; Katja Pfafferot, Royal Perth Hospital; Malte H.J. Heeg, University of Munich; Silvana Gaudieri, Royal Perth Hospital; Norbert Gruener, University of Munich; Andri Rauch, Royal Perth Hospital; Cheryl Day, Emory University
• Language: English
• Date: 2007-07-25
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2007 Lucas et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0000649
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 2
• Issue: 7
• Start Page: e649
• End Page: e649
• Grant/Funding Information: This work is part of the activities of the VIRGIL European Network of Excellence on Antiviral Drug Resistance supported by a grant (LSHM-CT-2004-503359) from the Priority 1 “Life Sciences, Genomics and Biotechnology for Health” programme in the 6th Framework Programme of the EU.; This work was supported by funding from the Wellcome Trust, the James Martin School of the 21st Century, Oxford and the Kompetenznetz Hepatitis HepNet (Teilprojekt 10.2.1).
• Keywords: Multidisciplinary Sciences; Science & Technology - Other Topics; Science & Technology
• Research Categories: Health Sciences, Immunology; Biology, Biostatistics

Abstract

Background. CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. Methodology/Prencipal Findings. Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. Conclusions/Significance. During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1 + patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.