Spontaneous resolution of the hepatitis C virus (HCV) infection depends on vigorous and early HCV-specific T cell responses. Of special importance are CD8 T cells, the main immune effector cells, which recognize antigens in an MHC class I-restricted manner and lyse infected hepatocytes. HCV-specific memory CD8 T cells persist in blood and liver for decades after HCV clearance and can mediate protective immunity. Accordingly, experimental depletion of CD8 T cells in chimpanzees delays HCV clearance until CD8 T cells reappear. A striking feature of HCV is its ability to establish persistence in the majority of infected persons. This is associated with a relatively late appearance of HCV-specific T cells in the infected liver. Although HCV RNA titers increase to high levels in the circulation within days of infection it takes two to three months for HCV-specific T cell responses to become detectable in the liver. This delayed intrahepatic appearance of HCV-specific T cells has been observed in assays in which T cells are subjected to in vitro expansion followed by functional assays and in ex vivo molecular assays such as microarray and real-time PCR. It has therefore been suggested that the delayed recruitment of HCV-specific T cells may cause the high incidence of HCV persistence. The mechanisms resulting in recruitment of HCV-specific CD8 T cells to the liver in acute HCV infection are not fully understood. It has been suggested that incomplete differentiation and maturation of HCV-specific T cells contribute to a defect in the expression of specific chemokine receptors on circulating HCV-specific T cells and thereby to delayed or impaired recruitment to the liver. It is also possible that there are defects in the specific intrahepatic events that are required for CD8 T cell recruitment, i.e. the induction of chemokines in the liver. This study was designed to analyze the kinetics and mechanisms of CD8 T cell recruitment from the blood to the liver during the incubation phase and the acute phase of HCV infection. Acute hepatitis C was established in chimpanzees, the sole animal model of HCV infection, with an intravenously injected, monoclonal HCV strain. This unique approach resulted in consistent virological and clinical courses of infection, providing a well-controlled setting for the analysis of early immunological events. As intrahepatic factors, we studied the kinetics of chemokine and chemokine receptor expression. As extrahepatic factors relevant to CD8 T cell recruitment, we determined the frequency of HCV-specific CD8 T cells as well as the expression of chemokine receptors by these T cells throughout the course of infection. Levels of the chemokines CXCL10, CXCL11, CCL4 and CCL5 increased in blood (cytometric bead array and EIA) and liver (real-time PCR) in all chimpanzees within a month of HCV inoculation. Chemokine induction correlated with induction of an intrahepatic type I interferon (IFN) response in vivo and was blocked by neutralizing antibodies against IFN-beta, in vitro. Despite the early-stage induction of chemokines, the intrahepatic lymphocytic infiltrate (determined by microscopy and real-time PCR) started to increase no earlier than 8 weeks after HCV infection, when HCV-specific, tetramer+ CD8+ T cells appeared in the circulation. The HCV-specific, tetramer+ CD8+ T cells expressed chemokine receptors when they were initially detected in blood samples, so they were recruitable to the liver as soon as they entered the circulation. These results demonstrate that specific chemokines are induced during early stages of HCV infection, which requires a type I IFN-mediated 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 clinical outcomes occur without evident differences in chemokine induction and T cell recruitment.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2011
Total Cost
$380,104
Indirect Cost
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State
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Bolte, Fabian J; O'Keefe, Ashley C; Webb, Lauren M et al. (2017) Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation. Gastroenterology 153:1392-1403.e2
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Bolte, Fabian J; Rehermann, Barbara (2017) Tissue-resident T cells in hepatitis B: A new target for cure? J Exp Med 214:1564-1566
Rehermann, Barbara (2017) Mature peritoneal macrophages take an avascular route into the injured liver and promote tissue repair. Hepatology 65:376-379
Rehermann, Barbara (2016) HCV in 2015: Advances in hepatitis C research and treatment. Nat Rev Gastroenterol Hepatol 13:70-2
Rehermann, Barbara (2016) Peptide-dependent HLA-KIR-mediated regulation of NK cell function. J Hepatol 65:237-9
Rehermann, Barbara (2015) Natural Killer Cells in Viral Hepatitis. Cell Mol Gastroenterol Hepatol 1:578-588
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Serti, Elisavet; Chepa-Lotrea, Xenia; Kim, Yun Ju et al. (2015) Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function. Gastroenterology 149:190-200.e2

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