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CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus†
Article first published online: 29 AUG 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 44, Issue 3, pages 736–745, September 2006
How to Cite
Puig, M., Mihalik, K., Tilton, J. C., Williams, O., Merchlinsky, M., Connors, M., Feinstone, S. M. and Major, M. E. (2006), CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus. Hepatology, 44: 736–745. doi: 10.1002/hep.21319
Potential conflict of interest: Nothing to report.
- Issue published online: 29 AUG 2006
- Article first published online: 29 AUG 2006
- Manuscript Accepted: 23 JUN 2006
- Manuscript Received: 21 DEC 2005
- National Vaccine Program Office
- National Cancer Institute. Grant Number: CA85883
Vol. 55, Issue 3, 983, Article first published online: 23 FEB 2012
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.)