Progression of human immunodeficiency virus (HIV) infection resulting in the development of AIDS, is associated with increased virus replication. Replication of HIV, in turn, is dependent on a number of cellular transcriptional factors that regulate viral RNA synthesis. Factors that interact with the enhancer present in the HIV long terminal repeat (LTR) are critical for activation of viral transcription. A number of factors that bind to HIV enhancer sequences have been identified, including an inducible binding activity called NF-kappaB which is composed of multiple polypeptides, several of which are members of the rel oncogene family. These include the p5O/NF-kappaB protein and the human c-rel protein. Another member of this family, v-rel, has recently been shown to inhibit NF-kappaB-mediated LTR activation. The objectives of this project are -to: 1) characterize the interactions between re/-family proteins and the HIV LTR; 2) examine the role that re/-related proteins play in the regulation of HIV replication and activation; and 3) identify novel NF-kappaB and re/-related proteins that may participate in HIV regulation. The information that will be gained from these studies will be used in the design and analysis of re/-related inhibitors of HIV expression. Studies of the interactions between re/-family proteins and the HIV LTR will involve mutagenesis of the v-rel, c-rel and NF-kappaB proteins to map the domains responsible for DNAbinding, dimerization and transcriptional activation of the HIV LTR. These mutants will be analyzed for their ability to activate or inhibit LTR function. The specific LTR sequences mediating rel transcriptional effects will be defined using mutant HIV LTRs containing alterations in the NFkappaB and Spl binding motifs. The role of re/-related proteins in the regulation of HIV replication will be studied in both productive viral replication and activation of latent proviruses in chronically-infected cells. The contributions of various re/-related proteins to HIV. expression will be analyzed in these systems, and the ability of mutant rel proteins to block HIV production will be tested. Finally, a series of low stringency hybridization and cloning experiments will be used to identify novel members of the rel/NF-kappaB family that may also regulate HIV expression.
|Effective start/end date||6/1/92 → 5/31/95|
- National Cancer Institute
- Infectious Diseases
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