Human immunodeficiency virus type 1 (HIV-1) encodes the transactivating protein Tat, which is essential for virus replication and progression of HIV disease. Tat has multiple domains and consequently the molecular mechanisms by which Tat regulates viral and cellular gene expression are complex. We have recently demonstrated that cellular activation by Tat involves a short core domain, Tat21-40, which contains seven cysteine residues highly conserved in most HIV-1 subtypes. Effective induction by Tat21-40 of both NF-kB-mediated HIV replication and TAR- dependent transactivation of the HIV-1 LTR indicates that this short sequence is sufficient to promote HIV infection. Moreover, Tat21-40 possesses potent angiogenic activity, further underscoring its role in HIV pathogenesis. These data provide the first demonstration that a 20- residue core domain sequence of Tat is sufficient to transactivate, induce HIV replication, and trigger angiogenesis. This short peptide sequence provides a potential novel therapeutic target for disrupting the functions of Tat and inhibiting progression of HIV disease. We have further demonstrated that Tat-dependent transcription takes place in a cell cycle-dependent manner and that Tat is capable of promoting gene expression in two distinct stages of the cell cycle. Tat-dependent LTR activation is observed in late G1/early S phase. This activation is TAR-dependent and requires a functional Sp1 binding site. A second phase of transactivation by Tat is observed in late G2, which is TAR- independent. This later phase of transcription is enhanced by a natural cell cycle blocker of HIV-1, vpr, which arrests infected cells at the G2/M boundary. Using a series of deletion constructs, we find that Tat- dependent G1/S activation is Sp1-dependent, whereas G2 activation is not. Our studies suggest that retroviral activators may perform distinct functions of activation during different stages of cell cycle. - AIDS, Cytokines, Gene regulation, protein structure, Retroviruses, Trans-acting Factors, Transcription, Virus-Cell Interactions,
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