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Increased Loss of CCR5⁺ CD45RA^– CD4⁺ T Cells in CD8⁺ Lymphocyte-Depleted Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana 70433,¹ Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115,² Division of Infectious Diseases, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611,³ Institute of Immunology, Technical University of Dresden, 01101 Dresden, Germany,⁴ AIDS Vaccine Program, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702,⁵ Department of Surgery, Duke University Medical Center, SORF Building, LaSalle Street Extension, Durham, North Carolina 27710,⁶ Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892⁷

Received 27 December 2007/ Accepted 11 March 2008

Previously we have shown that CD8⁺ T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4⁺ T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8⁺ T-cell responses on the magnitude of the CD4⁺ T-cell depletion, we investigated the effect of CD8⁺ lymphocyte depletion during primary SIV infection on CD4⁺ T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8⁺ lymphocyte-depletion changed the dynamics of CD4⁺ T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4⁺ T cells were restored to baseline levels. These CD4⁺ T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8⁺ lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5⁺ CD45RA^– CD4⁺ T cells in CD8⁺ lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4⁺ T cells were eliminated more efficiently in CD8⁺ lymphocyte-depleted animals. Also, CD8⁺ lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4⁺ T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8⁺ T-cell responses are absolutely critical to initiate at least partial control of SIV infection.

Published ahead of print on 26 March 2008.