Synergistic induction of apoptosis in primary CD4(+) T cells by macrophage-tropic HIV-1 and TGF-beta 1

Depletion of CD4(+) T lymphocytes is a central immunological characteristic of HIV-1 infection. Although the mechanism of such CD4(+) cell loss follow ing macrophage-tropic (R5) HIV-1 infection remains unclear, interactions be tween 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-beta1 enhanced expression of HIV chemokine coreceptors, the role of this host fac tor in virus effects was investigated using PBLs cultured in a nonmitogen-a dded system in the absence or presence of TGF-beta1. Most CD4 cells in such cultures had the phenotype CD25(-)CD69(-)DR(-)Ki67(-) and were CD45RO(brig ht)CD45(dim). 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-beta1, and this inhibition was accompanied by a loss of T cells from t he 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-beta1 despite the fact th at R5 HIV-1 depletes CD4(+) T cells in vivo. Increased apoptosis with HIV a nd TGF-beta1 was associated with reduced levels of Bcl-2 and increased expr ession of apoptosis-inducing factor, caspase-3, and cleavage of BID, c-IAP- 1, and X-linked inhibitor of apoptosis. These results show that TGF-beta1 p romotes depletion of CD4(+) T cells after R5 HIV-1 infection by inducing ap optosis and suggest that TGF-beta1 might contribute to the pathogenesis of HIV-1 infection in vivo.