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Journal of Virology, October 2007, p. 10861-10868, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00813-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Early Establishment and Antigen Dependence of Simian Immunodeficiency Virus-Specific CD8⁺ T-Cell Defects

Department of Microbiology and Immunology and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine,¹ Temple University College of Medicine, Philadelphia, Pennsylvania,² Emory University, Atlanta, Georgia,³ BIOQUAL, Rockville, Maryland⁴

Received 16 April 2007/ Accepted 23 July 2007

Differentiation and survival defects of human immunodeficiency virus (HIV)-specific CD8⁺ T cells may contribute to the failure of HIV-specific CD8⁺ T cells to control HIV replication. It is not known, however, whether simian immunodeficiency virus (SIV)-infected rhesus macaques show comparable defects in these virus-specific CD8⁺ T cells or when such defects are established during infection. Peripheral blood cells from acutely and chronically infected rhesus macaques were stained ex vivo for memory subpopulations and examined by in vitro assays for apoptosis sensitivity. We show here that SIV-specific CD8⁺ T cells from chronically SIV infected rhesus macaques show defects comparable to those observed in HIV infection, namely, a skewed CD45RA^– CD62L^– effector memory phenotype, reduced Bcl-2 levels, and increased levels of spontaneous and CD95-induced apoptosis of SIV-specific CD8⁺ T cells. Longitudinal studies showed that the survival defects and phenotype are established early in the first few weeks of SIV infection. Most importantly, they appear to be antigen driven, since most probably the loss of epitope recognition due to viral escape results in the reversal of the phenotype and reduced apoptosis sensitivity, something we observed also for animals treated with antiretroviral therapy. These findings further support the use of SIV-infected rhesus macaques to investigate the phenotypic changes and apoptotic defects of HIV-specific CD8⁺ T cells and indicate that such defects of HIV-specific CD8⁺ T cells are the result of chronic antigen stimulation.

Published ahead of print on 1 August 2007.

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