title: T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee.
abstract: Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection.
  
  
  CONCLUSIONS
  The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection.
authors: Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, OH.
authors: Benoit
authors: B
authors: Callendret
authors: Heather B
authors: HB
authors: Eccleston
authors: Shelby
authors: S
authors: Hall
authors: William
authors: W
authors: Satterfield
authors: Stefania
authors: S
authors: Capone
authors: Antonella
authors: A
authors: Folgori
authors: Riccardo
authors: R
authors: Cortese
authors: Alfredo
authors: A
authors: Nicosia
authors: Christopher M
authors: CM
authors: Walker
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D002679:Pan troglodytes; D012008:Recurrence; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase