Resting naïve CD4⁺ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques

Unlike HIV-1 and simian immunodeficiency virus (SIV), which induce a slow, unrelenting loss of immune function spanning several years, highly pathogenic simian-human immunodeficiency viruses (SHIVs) induce a rapid, complete, and irreversible depletion of CD4⁺ T lymphocytes in rhesus monkeys within weeks of infection, leading to death from immunodeficiency. We recently reported that, because these SHIVs exclusively use the CXCR4 coreceptor for cell entry, they target naïve CD4⁺ T cells for depletion in infected monkeys, whereas SIVs, which use CCR5, not CXCR4, cause the selective loss of memory CD4⁺ T lymphocytes in vivo. Here we show both by DNA PCR analyses and infectivity assays, using live sorted CD4⁺ T lymphocyte subsets, that 30-90% of circulating naïve cells were productively infected by day 10 after inoculation. This result implies that direct cell killing, not bystander apoptosis, is responsible for the massive loss of CD4⁺ T cells in the X4-tropic SHIV model. Furthermore, we directly demonstrate that >96% of virus producing cells did not express the Ki-67 proliferation marker on day 10 after inoculation using confocal microscopic analysis of lymph nodes samples. This finding is consistent with the prodigious levels of plasma viremia measured during acute X4-tropic SHIV infections of macaques being generated almost entirely by resting naïve CD4⁺ T cells.