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Hepatology 2006 Aug 29;44(3):736-45

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

Puig M, Mihalik K, Tilton JC, Williams O, Merchlinsky M, Connors M, Feinstone SM, Major ME

Major ME, US FDA, Div Viral Prod, Lab Hepatitis Viruses, Ctr Biol Evaluat & Res, Bldg 29A-Room 1D10-HFM,8800 Rockville Pike, Bethesda, MD 20892 USA US FDA, Div Viral Prod, Lab Hepatitis Viruses, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA NIAID, Immunoregulat Lab, NIH, Bethesda, MD USA US FDA, Ctr Biol Evaluat & Res, Viral Dis Lab, Bethesda, MD USA

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. (HEPATOLOGY 2006;44:736-745.).


Category: Journal Article
PubMed ID: #16941702
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2013-01-06
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