The goal of this project is the understanding of the role of viral-cellular interactions in the regulation of gene expression of the human immunodeficiency virus (HIV). In particular, we have examined the role of cis-acting DNA sequences in the HIV long terminal repeat (LTR) in the control of HIV gene expression in both chronic or latent infections and in acute infection of human T lymphocytes. In the ACH2 cell line, a model of chronic HIV infection, HIV expression can be activated by treatment with the cytokine, tumor necrosis factor a (TNF-alpha). TNF-alpha activates HIV through induction of the cellular transcriptional factor, NF-kappa-B, that binds to the HIV LTR. We have also studied the effect of the LTR regulatory sequences on the acute viral replication by mutating regulatory sequences in the LTR of an infectious molecular clone. These studies have shown that the NF-kappa-B binding sites are not essential for HIV replication in human T cells. The Spl binding sites are not required for HIV replication in some T cell lines; however, they seem to be required for viral growth in T cells lacking the NF-kappa-B protein. These studies have also shown that a mutation in the TAR region that blocks tat transactivation destroys HIV infectivity. Thus, the different protein binding sites in the LTR may play distinct roles in the infection of different human cells; however, the interaction of tat and TAR is critical for HIV infectivity. Finally, recent studies in our laboratory have identified the presence of a DNA sequence in the HIV tat coding region that functions as an enhancer element in a variety of human cells. The importance of this sequence in HIV replication has not been determined.
