The work proposed here has the long-term objective of contributing to the treatment of people with AIDS. We believe that if we develop a deep enough understanding of the molecular biology of HIV growth, we will uncover new targets for anti-retroviral therapy.
The specific aims of the program are: 1) to understand the interaction of the NF-kappaB transcription factor with its binding site in the HIV genome and in cellular genes; 2) to understand whether RelB plays a negative role in the transcription of the HIV genome; 3) to identify and clone the genes for the proteins that are involved in making T cells a fertile soil for the growth of HIV. The proposal derives from the understanding that NF-kappaB is a critical transcription factor for expression of the HIV genome.
For Aim 1, we will use novel technologies we have recently developed to determine exactly which components of the NF-kappaB family of proteins are responsible for the activity of the factor. We will also extend this work to the study of the cellular genes activated when T cells move from a quiescent state to an active state, a transition from resistance to HIV to permissiveness for viral growth. We wish to understand not only what proteins are involved but also why different genes use subtly different binding sites, and why different stimuli for NF-kappaB activation might lead to different protein requirements on a single DNA site.
Aim 2 derives from our recent demonstration that one of the Rel- related subunits that compose NF-kappaB, RelB, plays a negative role in regulation. It can establish thresholds for activation as well as down-regulating transcription of genes that have responded to NF-kappaB.
For Aim 3 we will attempt to find new proteins that function on the pathways that lead to activation of HIV permissivity and the concomitant receptor stimulation of latent HIV genomes. Although individual pathways are known to be used by particular activators, like T cell receptor stimulation or tumor necrosis factor, no one pathway is fully elucidated. For this we will use a novel screening methodology to find and ultimately characterize new proteins that lead to transcription of the HIV genome.
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