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Effect of CD8⁺ Lymphocyte Depletion on Virus Containment after Simian Immunodeficiency Virus SIVmac251 Challenge of Live Attenuated SIVmac2393-Vaccinated Rhesus Macaques

Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,¹ New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, and Massachusetts General Hospital, Charlestown, Massachusetts 02129,² Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30322,³ Primedica Corporation, Worcester, Massachusetts 01536,⁴ Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702,⁵ Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany,⁶ Institute of Immunology, Technical University of Dresden, Dresden, Germany,⁷ Beckman Coulter, San Diego, California 92121,⁸ Department of Biostatistical Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,⁹ Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710,¹⁰ Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,¹¹

Received 16 September 2004/ Accepted 7 March 2005

Although live attenuated vaccines can provide potent protection against simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus challenges, the specific immune responses that confer this protection have not been determined. To test whether cellular immune responses mediated by CD8⁺ lymphocytes contribute to this vaccine-induced protection, we depleted rhesus macaques vaccinated with the live attenuated virus SIVmac2393 of CD8⁺ lymphocytes and then challenged them with SIVmac251 by the intravenous route. While vaccination did not prevent infection with the pathogenic challenge virus, the postchallenge levels of virus in the plasmas of vaccinated control animals were significantly lower than those for unvaccinated animals. The depletion of CD8⁺ lymphocytes at the time of challenge resulted in virus levels in the plasma that were intermediate between those of the vaccinated and unvaccinated controls, suggesting that CD8⁺ cell-mediated immune responses contributed to protection. Interestingly, at the time of challenge, animals expressing the Mamu-A*01 major histocompatibility complex class I allele showed significantly higher frequencies of SIV-specific CD8⁺ T-cell responses and lower neutralizing antibody titers than those in Mamu-A*01^– animals. Consistent with these findings, the depletion of CD8⁺ lymphocytes abrogated vaccine-induced protection, as judged by the peak postchallenge viremia, to a greater extent in Mamu-A*01⁺ than in Mamu-A*01^– animals. The partial control of postchallenge viremia after CD8⁺ lymphocyte depletion suggests that both humoral and cellular immune responses induced by live attenuated SIV vaccines can contribute to protection against a pathogenic challenge and that the relative contribution of each of these responses to protection may be genetically determined.

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