CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus

Authors

  • Montserrat Puig,

    1. Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Kathleen Mihalik,

    1. Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • John C. Tilton,

    1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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  • Ollie Williams,

    1. Laboratory of Viral Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Michael Merchlinsky,

    1. Laboratory of Viral Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Mark Connors,

    1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
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  • Stephen M. Feinstone,

    1. Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
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  • Marian E. Major

    Corresponding author
    1. Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD
    • Laboratory of Hepatitis Viruses, Division of Viral Products, Bldg. 29A/Room 1D10/HFM 448, 8800 Rockville Pike, Bethesda, MD 20892
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    • fax: (301) 402-5585.

Errata

This article is corrected by:

  1. Errata: Correction Volume 55, Issue 3, 983, Article first published online: 23 February 2012

  • Potential conflict of interest: Nothing to report.

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-γ 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. (HEPATOLOGY 2006;44:736–745.)

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