title: Delayed induction, not impaired recruitment, of specific CD8⁺ T cells causes the late onset of acute hepatitis C.
abstract: OBJECTIVE
  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 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 outcomes occur without evident differences in chemokine induction and T-cell recruitment.
authors.affiliation: Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.forename: Su-Hyung
authors.initials: SH
authors.lastname: Park
authors.forename: Mary
authors.initials: M
authors.lastname: Demino
authors.forename: Michelina
authors.initials: M
authors.lastname: Nascimbeni
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mihalik
authors.forename: Marian
authors.initials: M
authors.lastname: Major
authors.forename: Naga S
authors.initials: NS
authors.lastname: Veerapu
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Feinstone
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism; D018925:Chemokines / Q000097:blood / Q000276:immunology*; D006526:Hepatitis C / Q000097:blood / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism; D023421:Models, Animal; D002679:Pan troglodytes; D012333:RNA, Messenger / Q000378:metabolism*; D012367:RNA, Viral / Q000097:blood / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019562:Viral Load
chemical_list: D000906:Antibodies; D015704:CD4 Antigens; D016827:CD8 Antigens; D018925:Chemokines; D012333:RNA, Messenger; D012367:RNA, Viral; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016899:Interferon-beta; D007371:Interferon-gamma; D000410:Alanine Transaminase