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


RESULTS
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
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.
Lucas
Michaela
M
Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia.
Ulsenheimer
Axel
A
Pfafferot
Katja
K
Heeg
Malte H J
MH
Gaudieri
Silvana
S
Grüner
Norbert
N
Rauch
Andri
A
Gerlach
J Tilman
JT
Jung
Maria-Christina
MC
Zachoval
Reinhart
R
Pape
Gerd R
GR
Schraut
Winfried
W
Santantonio
Teresa
T
Nitschko
Hans
H
Obermeier
Martin
M
Phillips
Rodney
R
Scriba
Thomas J
TJ
Semmo
Nasser
N
Day
Cheryl
C
Weber
Jonathan N
JN
Fidler
Sarah
S
Thimme
Robert
R
Haberstroh
Anita
A
Baumert
Thomas F
TF
Klenerman
Paul
P
Diepolder
Helmut M
HM
D000208:Acute Disease; D000595:Amino Acid Sequence; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005838:Genotype; D015798:HLA-DR1 Antigen / Q000737:chemistry / Q000276:immunology; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008099:Liver / Q000276:immunology / Q000821:virology; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000821:virology*; D014764:Viral Proteins / Q000032:analysis / Q000737:chemistry / Q000276:immunology
D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte; D015798:HLA-DR1 Antigen; D010446:Peptide Fragments; D014764:Viral Proteins