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Delayed induction, not impaired recruitment, of specific CD8+ T cells causes the late onset of acute hepatitis C
E. Shin, S. Park, M. Demino, M. Nascimbeni, K. Mihalik, M. Major, , T. Heller, S.M. Feinstone, C.M. RiceShow More
Published in W.B. Saunders
Volume: 141
Issue: 2
Pages: 686 - 695.e1
Background & Aims: Hepatitis C virus (HCV) infection is characterized by lack of immune-mediated liver injury despite a high level of HCV replication during the incubation phase, which lasts about 8 weeks. We investigated whether this results from delayed recruitment of HCV-specific T cells and whether it facilitates HCV persistence. Methods: Six chimpanzees were infected with HCV; blood and liver samples were collected for 28 weeks and analyzed for immune cells and chemokines. Results: Two chimpanzees developed self-limited infections, whereas the remaining 4 developed chronic infections. Levels of the chemokines CXCL10, CXCL11, CCL4, and CCL5 increased in blood and liver samples from all chimpanzees within 1 month of HCV infection. Chemokine induction correlated with intrahepatic type I interferon (IFN) responses in vivo and was blocked by neutralizing antibodies against IFN-β in vitro. Despite the early-stage induction of chemokines, the intrahepatic lymphocytic infiltrate started to increase no earlier than 8 weeks after HCV infection, when HCV-specific, tetramer-positive CD8+ T cells appeared in the circulation. The HCV-specific CD8+ T cells expressed chemokine receptors when they were initially detected in blood samples, so they could be recruited to the liver as soon as they entered the circulation. Conclusions: Chemokines are induced during early stages of HCV infection, which requires a type I IFNmediated response. The delayed onset of acute hepatitis does not result from delayed recruitment of HCV-specific T cells, but could instead be related to a primary delay in the induction of HCV-specific T cells. Divergent outcomes occur without evident differences in chemokine induction and T-cell recruitment. © 2011 AGA Institute.
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Published in W.B. Saunders
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