The Tat protein of the human immunodeficiency virus acts to stimulate transcription of the integrated proviral genome and also affects T-cell activation and apoptosis during infection. Because of this pivotal role during infection, it is generally believed that inhibition of Tat function will be of therapeutic benefit to HIV-infected individuals. To rationally develop specific Tat inhibitors, it will be necessary to identify cellular factors that mediate Tat function and to gain an understanding of the role of these factors in normal physiology and in HIV infection. Recent work by several laboratories has demonstrate that a cellular protein kinase, named TAK (Tat associated kinase), mediates Tat function. TAK is composed of more than one subunit and it is closely related to a transcriptional elongation factor termed pTEFb that was first identified in Drosophila melanogaster nuclear extracts. The catalytic subunit of TAK is a kinase called PITALRE, a member of the cyclin-dependent family of protein kinases (CDKs). Prior to its identification as a component of TAK, no specific function had been ascribed to PITALRE. TAK probably mediates Tat transcriptional activation by phosphorylating the carboxy terminal domain (CTD) of RNA polymerase II in a manner that stimulates transcriptional elongation. Additionally, TAK was found recently to be induced in activated primary human CD4+ T-cells and in promonocytic cell lines induced to differentiate to macrophages, suggesting that TAK may normally have an important function in the host cells of HIV infection. It is proposed to continue studies on regulation of TAK function and mechanisms of transcriptional activation by TAK. It is also proposed to extend studies of TAK into a new and important area by investigation TAK's normal role in T-cells and macrophages, the two major host cells of human immunodeficiency virus infection. The completion of the proposed research should provide insight into Tat and TAK and will be important background for future development of therapeutic strategies directed against Tat function.
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