The long-term objective of this proposal is to develop the first class of small molecule, orally-bioavailable drugs that increases T cell production from the thymus and enhances immune reconstitution in AIDS and other immunodeficiencies. About 40 million individuals are currently infected with HIV. Combined antiviral therapies for HIV (e.g. HAART) have revolutionized the treatment of AIDS by suppressing blood levels of virus to below detectable levels. Even though control of opportunistic infections is greatly improved, HIV generally retums to pretreatment levels if antiviral therapy is stopped. Enhanced immune control of HIV following HAART has proved elusive except for patients treated very soon alter infection. New T cell production from the thymus is believed to contribute to immune reconstitution during HAART. Therapeutic stimulation of thymic T cell (or thymocyte) production will increase immune diversity and fill gaps created by HIV infection that prevent its control. Better immune reconstitution could reduce the requirement for antiviral therapy, with its attendant long-term side effects, and greatly improve the chances that a therapeutic vaccine for HIV can be effective. The orphan nuclear receptor RORgamma specifically controls the production and survival of the major thymocyte cell type, the DP thymocyte, that is involved in creation and selection of new T cell receptors. An agonist to RORgamma is predicted to markedly enhance DP thymocyte survival, and, over the long term, to increase immune diversity. Nuclear receptors have historically been successful targets for small molecule drug discovery, but ligands have yet to be identified for RORgamma. This Phase 1 effort proposes to (1) optimize and establish functionally-overlapping assays for RORgamma to enable discovery of authentic ligands while rejecting false positives; (2) identify potential ligands in focused small molecule libraries obtained through partnership and purchase; and (3) confirm activity in cell-based assays of thymocyte function. Phase 1 lays the foundation for further screening and directed synthesis of specific, high affinity ligands to RORgamma in Phase 2 for pre-clinical proof-of-principle studies.
