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1
Laboratory of Gene Regulation, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Bethesda, MD 20892
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-
1 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-1. 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-1,
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-1
despite the fact that R5 HIV-1 depletes CD4+ T cells in
vivo. Increased apoptosis with HIV and TGF-1 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-1 promotes
depletion of CD4+ T cells after R5 HIV-1 infection by
inducing apoptosis and suggest that TGF-1 might contribute to the
pathogenesis of HIV-1 infection in vivo.
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