HIV-1-infected people manifest a gradual decline in CD4+ T cells, which is initially offset by a rise in CD8+ T Cells. At the T cell inflection point, levels of CD8+ T cells (and total CD3+ T cells) start to fall, leading to AIDS. The emergence of CXCR4-tropic strains of HIV often precedes this inflection point, suggesting that these strains effect T cell homeostasis failure by inducing death in naïve CD4+ and CD8+ T cells. To test this hypothesis, T-cells from HIV-negative and HIV-positive donors were exposed to Aldrithiol-inactivated HIV-1 virions which retain the conformation of intact virions but are not infectious. Flow cytometry-based methods for measuring cell death (Annexin V staining) and cell survival in vitro were employed. Cultures exposed to both types of virions exhibited higher levels of cell death than cultures exposed to media alone or to media from which virions had been depleted (mock virions). Exposure to CXCR4-tropic virions resulted in greater percentages of Annexin V-positive naïve T cells than exposure to CCR5-tropic virions in some cells from some donors: It was found in naïve CD4+ T cells from one 1/3 HIV-negative donors, naïve CD8+ T cells from 2/4 HIV-negative donors, and 2/3 HIV-positive donors. Peripheral blood mononuclear cells exposed to virions did not express CD25, CD69, TNFRI or TNFRII, but did express CD95, CD95L, HLA-DR, CD31 and PD-1. After 7 days of culture, naïve CD8+ T cells were scarcer in cultures treated with CXCR4-tropic virions (42.7±7%) than in cultures treated with CCR5-tropic virions (58.9±15.4%). Macrophage depletion of cultures generally increased percentages of Annexin V positive cells. There was an increased decline in cell numbers in cells from HIV-positive donors. Among naïve and memory/terminal effector subsets of CD4+ and CD8+ T cells purified by flow cytometry, naïve CD4+ T cells declined significantly faster in cultures treated with CXCR4-tropic virions than with CCR5-tropic virions (P=0.013). Thus, CXCR4-tropic virions sometimes induce more cell death than CCR5 tropic virions in naïve CD4 and naïve CD8 T cells, and may contribute to failure of T cell homeostasis in HIV-infected persons.