Synergistic Induction of Apoptosis in Primary CD4+ T Cells by Macrophage-Tropic HIV-1 and TGF-β1

Abstract

Depletion of CD4+ T lymphocytes is a central immunological characteristic of HIV-1 infection. Although the mechanism of such CD4+ cell loss following macrophage-tropic (R5) HIV-1 infection remains unclear, interactions between viral and host cell factors are thought to play an important role in the pathogenesis of HIV-1 disease. Based on the observation that TGF-β1 enhanced expression of HIV chemokine coreceptors, the role of this host factor in virus effects was investigated using PBLs cultured in a nonmitogen-added system in the absence or presence of TGF-β1. Most CD4 cells in such cultures had the phenotype CD25−CD69−DR−Ki67− and were CD45RObrightCD45RAdim. Cultured cells had increased expression of CCR5 and CXCR4 and supported both HIV-1 entry and completion of viral reverse transcription. Virus production by cells cultured in the presence of IL-2 was inhibited by TGF-β1, and this inhibition was accompanied by a loss of T cells from the culture and an increase in CD4+ T cell apoptosis. Whereas R5X4 and X4 HIV-1 infection was sufficient to induce T cell apoptosis, R5 HIV-1 failed to induce apoptosis of PBLs in the absence of TGF-β1 despite the fact that R5 HIV-1 depletes CD4+ T cells in vivo. Increased apoptosis with HIV and TGF-β1 was associated with reduced levels of Bcl-2 and increased expression of apoptosis-inducing factor, caspase-3, and cleavage of BID, c-IAP-1, and X-linked inhibitor of apoptosis. These results show that TGF-β1 promotes depletion of CD4+ T cells after R5 HIV-1 infection by inducing apoptosis and suggest that TGF-β1 might contribute to the pathogenesis of HIV-1 infection in vivo.