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Generation of CD3⁺CD8^low Thymocytes in the HIV Type 1-Infected Thymus¹

Mary E. Keir^2,*, Michael G. Rosenberg, Johan K. Sandberg, Kimberly A. Jordan, Andrew Wiznia, Douglas F. Nixon, Cheryl A. Stoddart and Joseph M. McCune^3,,

^* Biomedical Sciences Graduate Program, Departments of Medicine, and Microbiology and Immunology, and Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94143; and Pediatric Consultation Services, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461

Infection with the HIV type 1 (HIV-1) can result both in depletion of CD4⁺ T cells and in the generation of dysfunctional CD8⁺ T cells. In HIV-1-infected children, repopulation of the peripheral T cell pool is mediated by the thymus, which is itself susceptible to HIV-1 infection. Previous work has shown that MHC class I (MHC I) molecules are strongly up-regulated as result of IFN- secretion in the HIV-1-infected thymus. We demonstrate in this study that increased MHC I up-regulation on thymic epithelial cells and double-positive CD3^-/intCD4⁺CD8⁺ thymocytes correlates with the generation of mature single-positive CD4^-CD8⁺ thymocytes that have low expression of CD8. Treatment of HIV-1-infected thymus with highly active antiretroviral therapy normalizes MHC I expression and surface CD8 expression on such CD4^-CD8⁺ thymocytes. In pediatric patients with possible HIV-1 infection of the thymus, a low CD3 percentage in the peripheral circulation is also associated with a CD8^low phenotype on circulating CD3⁺CD8⁺ T cells. Furthermore, CD8^low peripheral T cells from these HIV-1⁺ pediatric patients are less responsive to stimulation by Ags from CMV. These data indicate that IFN--mediated MHC I up-regulation on thymic epithelial cells may lead to high avidity interactions with developing double-positive thymocytes and drive the selection of dysfunctional CD3⁺CD8^low T cells. We suggest that this HIV-1-initiated selection process may contribute to the generation of dysfunctional CD8⁺ T cells in HIV-1-infected patients.

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