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Live Attenuated Lentivirus Infection Elicits Polyfunctional Simian Immunodeficiency Virus Gag-Specific CD8⁺ T Cells with Reduced Apoptotic Susceptibility in Rhesus Macaques that Control Virus Replication after Challenge with Pathogenic SIVmac239¹

Meritxell Genescà^*,, Tracy Rourke^*,, Jun Li^*,, Kristen Bost^*,, Barinderpaul Chohan^*,, Michael B. McChesney and Christopher J. Miller^2,*,,,

^* Center for Comparative Medicine, California National Primate Research Center, Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, and Division of Infectious Diseases, School of Medicine, University of California, Davis, CA 95616

HIV-specific CD8⁺ T cells that secrete multiple cytokines in response to Ag stimulation are associated with the control of virus replication during chronic HIV infection. To determine whether the presence of polyfunctional CD8⁺ T cell responses distinguishes protected and unprotected monkeys in a live attenuated lentivirus model, SIV Gag peptide-specific CD8⁺ T cell responses of simian HIV (SHIV) 89.6-vaccinated, SIVmac239-challenged rhesus macaques were compared in two monkeys that controlled challenge virus replication and two that did not. The ratio of Bcl-2⁺ Gag-specific CD8⁺ T cells to caspase-3⁺ Gag-specific CD8⁺ T cells was higher in the vaccinated-protected animals compared with unprotected monkeys. In addition, polyfunctional SIV-specific CD8⁺ T cells were consistently detected through 12 wk postchallenge in the protected animals but not in the unprotected animals. In the unprotected monkeys, there was an increased frequency of CD8⁺ T cells expressing markers associated with effector memory T cells. Further, there was increased annexin V expression in central memory T cells of the unprotected animals before challenge. Thus, monkeys that control viral replication after live attenuated SHIV infection have polyfunctional SIV-specific CD8⁺ T cells with an increased survival potential. Importantly, the differences in the nature of the SIV-specific CD8⁺ T cell response in the protected and unprotected animals are present during acute stages postchallenge, before different antigenic levels are established. Thus, the polyfunctional capacity and increased survival potential of CD8⁺ SIV-specific T cells may account for live attenuated, SHIV89.6-mediated protection from uncontrolled SIV replication.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Services Grants RR00169 from the National Center for Research Resources and P01 AI066314 and R01 AI44480 from the National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Christopher J. Miller, California National Primate Research Center (CNPRC), University of California, One Shields Avenue, Davis, CA 95616. E-mail address: cjmiller{at}ucdavis.edu

³ Abbreviations used in this paper: vRNA, viral RNA; 7-AAD, 7-aminoactinomycin D; Bcl-2, B-cell lymphoma/leukemia-2; CM, central memory; EM, effector memory; LNMC, lymph node mononuclear cell; PC, postchallenge; SFC, spot-forming cell; SHIV, simian human immunodeficiency virus.

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