Tracking virus-specific CD4+ T cells during and after acute hepatitis C virus infection.

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.