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

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.