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| Article Authors: | Montserrat Puig; Kathleen Mihalik; John C Tilton; Ollie Williams; Michael Merchlinsky; Mark Connors; Stephen M Feinstone; Marian E Major |
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| Article Title: | CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus. |
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| Reference ID: | 1002138 |
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| 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. |
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| Affiliations: | Laboratory of Hepatitis Viruses, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. |
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| Date: | 2006 |
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| Reference Type: | Literature |
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| PubMed ID: | 16941702 |
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| Journal: | Hepatology |
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| Journal Volume: | 44 |
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| Article Pages: | 736-45 |
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| Journal ISSN: | 1527-3350 |
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| Article Chemical List: | Hepatitis C Antigens;Viral Hepatitis Vaccines |
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| Article MeSH List: | Animals; Ape Diseases(immunology; prevention & control); CD4-Positive T-Lymphocytes(drug effects; immunology); Hepacivirus(immunology; physiology); Hepatitis C(immunology; prevention & control; veterinary); Hepatitis C Antigens(immunology); Lymphocyte Activation; Pan troglodytes; Treatment Outcome; Vaccination(methods); Viral Hepatitis Vaccines(therapeutic use); Virus Replication |
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| Curation Last Updated: | 2011-10-24 22:27:00 |
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