CD8⁺ cell depletion of SHIV89.6P-infected macaques induces CD4⁺ T cell proliferation that contributes to increased viral loads

Previous studies have shown that depletion of CD8⁺ cells during acute and chronic simian immunodeficiency virus (SIV) infection leads to increased viral replication, morbidity, and mortality, which have been attributed to loss of CD8⁺ T cell-mediated control of SIV. However, these studies did not exclude that CD8⁺ cell depletion increased homeostatic proliferation of CD4⁺ T cells, resulting in increased viral targets and, therefore, viral rebound. Chronically SHIV89.6P-infected cynomolgus macaques were CD8⁺ cell-depleted, and the frequency, cell number, and phenotype of CD4⁺ T cells and viral infection were examined using flow cytometry and quantitative real-time PCR. The frequency and number of Ki-67-expressing CD4⁺ T cells were increased with CD8 ⁺ cell depletion. This proliferation of CD4⁺ T cells occurred even in animals with no rebound of viral loads. Most of the proliferating cells were effector memory CD4⁺ T cells. Plasma simian HIV (SHIV) RNA copies positively correlated with proliferating CD4⁺ T cells and SHIV DNA copies in Ki-67⁺ CD4⁺ T cells. Although this study does not exclude an important role for virus-specific CD8⁺ T cells in SIV and SHIV infection, our data suggest that homeostatic proliferation is an important contributor to increases in plasma viremia that follow CD8⁺ cell depletion.