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Lucas, Michaela; Ulsenheimer, Axel; Pfafferot, Katja; Heeg, Malte H. J.; Gaudieri, Silvana; Grüner, Norbert; Rauch, Andri; Gerlach, J. Tilman; Jung, Maria-Christina; Zachoval, Reinhart; Pape, Gerd R.; Schraut, Winfried; Santantonio, Teresa; Nitschko, Hans; Obermeier, Martin; Phillips, Rodney; Scriba, Thomas J.; Semmo, Nasser; Day, Cheryl; Weber, Jonathan N.; Fidler, Sarah; Thimme, Robert; Haberstroh, Anita; Baumert, Thomas F.; Klenerman, Paul; Diepolder, Helmut M. (2007): Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.
In: PloS one (7), e649




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. 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. 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.