Defining the mechanisms of action of drug candidates that can reactivate latent proviruses presents formidable challenges both because studies ofthe physiological mechanisms responsible for proviral reactivation are incomplete and because there are no universally accepted primary cell models for HIV and SIV latency that can be used to support the development of new drugs. This project has been designed to address these critical Collaboratory strategic needs by defining how the sequential activation of multiple signaling pathways modifies the duration and magnitude ofthe HIV transcriptional response in primary cell models for HIV latency and by defining the role of the accessory protein Nef in establishing and maintaining HIV and SIV latency. We hypothesize that sustained HIV proviral reactivation minimally requires both the activation of P-TEFb and the sequential activation of NF-Kappa B, NFAT and AP-1. As part of our further development ofthe primary cell model we have recently made the surprising and discovery that proviral silencing is strongly enhanced in cells infected with viruses expressing Nef. We hypothesize that disruption of cell signaling pathways by Nef creates an environment that promotes viral entry into latency. Since Nef has long been known to enhance viral replication and spread, the obsen/ation that Nef also increases the frequency of HIV silencing raises the intriguing possibility that proviral latency is an important mechanism used to disseminate viruses eariy during infections and to escape the strong immune responses mounted during acute infections. In the course of these studies we will be interacting closely with other Collaboratory investigators. Key interactions will include the detailed evaluation of candidate drugs in our pipeline (Hazuda), development of latency models in primary cells (Planelles), development of latency models for SIV (Clements), and evaluation of new cellijlar factors that contribute to the maintenance of HIV latency (Greene, Verdin, Ofi and Peteriin).
This proposal forms an integral part ofthe basic science program ofthe Collaboratory. Specifically, the proposal will develop new techniques for evaluating drug candidates and explore an unexpected mechanism involving HIV Nef that forces HIV entry into latency.
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