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Immunodomination in the Evolution of Dominant Epitope-Specific CD8⁺ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys¹

Michael H. Newberg^*, Kimberly J. McEvers^*, Darci A. Gorgone^*, Michelle A. Lifton^*, Susanne H. C. Baumeister^*, Ronald S. Veazey, Jörn E. Schmitz^* and Norman L. Letvin^2,*

^* Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and Tulane National Primate Research Center, Covington, LA 70433

Because the control of HIV-1 replication is largely dependent on CD8⁺ T lymphocyte responses specific for immunodominant viral epitopes, vaccine strategies that increase the breadth of dominant epitope-specific responses should contribute to containing HIV-1 spread. Developing strategies to elicit such broad immune responses will require an understanding of the mechanisms responsible for focusing CD8⁺ T lymphocyte recognition on a limited number of epitopes. To explore this biology, we identified cohorts of rhesus monkeys that expressed the MHC class I molecules Mamu-A*01, Mamu-A*02, or both, and assessed the evolution of their dominant epitope-specific CD8⁺ T lymphocyte responses (Gag p11C- and Tat TL8-specific in the Mamu-A*01⁺ and Nef p199RY-specific in the Mamu-A*02⁺ monkeys) following acute SIV infection. The Mamu-A*02⁺ monkeys that also expressed Mamu-A*01 exhibited a significant delay in the evolution of the CD8⁺ T lymphocyte responses specific for the dominant Mamu-A*02-restricted SIV epitope, Nef p199RY. This delay in kinetics was not due to differences in viral load kinetics or magnitude or in viral escape mutations, but was associated with the evolution of the Mamu-A*01-restricted CD8⁺ T lymphocyte responses to the highly dominant SIV epitopes Gag p11C and Tat TL8. Thus, the evolution of dominant epitope-specific CD8⁺ T lymphocyte responses can be suppressed by other dominant epitope-specific responses, and this immunodomination is important in determining the kinetics of dominant epitope-specific responses.

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