title: CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus.
abstract: Hepatitis C is a major cause of chronic liver disease, with 170 million individuals infected worldwide and no available vaccine. We analyzed the effects of an induced T-cell response in 3 chimpanzees, targeting nonstructural proteins in the absence of neutralizing antibodies. In all animals the specific T-cell response modified the outcome of infection, producing a 10- to 1,000-fold reduction in peak virus titers. The challenge of 2 immunized animals that had been previously exposed to hepatitis C virus resulted in subclinical infections. Immune responses in the third animal, naive prior to immunization, limited viral replication immediately, evidenced by a 30-fold reduction in virus titer by week 2, declining to a nonquantifiable level by week 6. After 10 weeks of immunological control, we observed a resurgence of virus, followed by progression to a persistent infection. Comparing virus evolution with T-cell recognition, we demonstrated that: (i) resurgence was concomitant with the emergence of new dominant viral populations bearing single amino acid changes in the NS3 and NS5A regions, (ii) these mutations resulted in a loss of CD4+ T-cell recognition, and (iii) subsequent to viral resurgence and immune escape a large fraction of NS3-specific T cells became impaired in their ability to secrete IFN-gamma and proliferate. In contrast, NS3-specific responses were sustained in the recovered/immunized animals presenting with subclinical infections. In conclusion, viral escape from CD4+ T cells can result in the eventual failure of an induced T-cell response that initially controls infection. Vaccines that can induce strong T-cell responses prior to challenge will not necessarily prevent persistent HCV infection.
authors.affiliation: Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Puig
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mihalik
authors.forename: John C
authors.initials: JC
authors.lastname: Tilton
authors.forename: Ollie
authors.initials: O
authors.lastname: Williams
authors.forename: Michael
authors.initials: M
authors.lastname: Merchlinsky
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Feinstone
authors.forename: Marian E
authors.initials: ME
authors.lastname: Major
mesh_terms: D000818:Animals; D018420:Ape Diseases / Q000276:immunology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D006526:Hepatitis C / Q000276:immunology / Q000517:prevention & control* / Q000662:veterinary; D018936:Hepatitis C Antigens / Q000276:immunology*; D008213:Lymphocyte Activation; D002679:Pan troglodytes; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods*; D014761:Viral Hepatitis Vaccines / Q000627:therapeutic use*; D014779:Virus Replication
chemical_list: D018936:Hepatitis C Antigens; D014761:Viral Hepatitis Vaccines