Project Grant R01DA060761

POSITIVE ALLOSTERIC MODULATOR PNU-120596 TO TREAT HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS - ABSTRACT HIV INFECTION OF THE CENTRAL NERVOUS SYSTEM (CNS) OCCURS IN A MAJORITY OF HIV-INFECTED INDIVIDUALS. IT CAUSES HIV- ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) EVEN IN THE ERA OF COMBINATION ANTIRETROVIRAL THERAPY (CART). THERE ARE CURRENTLY NO THERAPIES FOR HAND. WE HAVE FOCUSED ON HIV INFECTION AND PATHOGENESIS IN THE CNS OVER THE PAST 25 YEARS. OUR STUDIES HAVE HELPED ESTABLISH CELL-FREE AND CELL-CELL CONTACT-MEDIATED HIV INFECTION OF ASTROCYTES AND A CRITICAL ROLE OF HIV TAT PROTEIN IN HIV NEUROPATHOGENESIS. THE LATTER INCLUDES THE CREATION OF DOXYCYCLINE-INDUCIBLE BRAIN-SPECIFIC HIV TAT TRANSGENIC MICE (ITAT) AS AN IMPORTANT SURROGATE HAND MODEL. WE HAVE RECENTLY UNCOVERED THAT ACTIVATION OF A7 NICOTINIC ACETYLCHOLINE RECEPTOR (NACHR) BY ITS POSITIVE ALLOSTERIC MODULATOR (PAM) PNU-120596 AMELIORATES HAND NEUROLOGY AND NEUROPATHOLOGY USING THE ITAT MODEL, SUGGESTING THE THERAPEUTIC POTENTIAL OF A7 NACHR PAM AGAINST HAND. THESE STUDIES ARE SIGNIFICANT BECAUSE TAT PROTEIN CONTINUES TO BE DETECTED IN THE BRAIN OF HIV-INFECTED INDIVIDUALS TREATED WITH CART. IN ADDITION, WE HAVE SHOWN THAT A7 NACHR PAM INHIBITS HIV REPLICATION AND REACTIVATION. THESE FINDINGS UNDOUBTEDLY CALL FOR FURTHER CHARACTERIZATION OF THE MECHANISMS OF A7 NACHR PAM-MEDIATED NEUROPROTECTION AGAINST TAT NEUROTOXICITY AND THE MECHANISMS BY WHICH A7 NACHR PAM ACTIVATION LEADS TO INHIBITION OF HIV REPLICATION AND REACTIVATION. THE CENTRAL HYPOTHESIS FOR THIS PROPOSAL IS THAT A7 NACHR PAM HOLD GREAT PROMISE AS CART ADJUNCTIVE THERAPEUTICS TO TREAT HIV NEUROPATHOGENESIS AND HAND. TO TEST THIS HYPOTHESIS, WE PROPOSE THE FOLLOWING THREE INTERRELATED SPECIFIC AIMS: (1) TO FURTHER CHARACTERIZE THE MECHANISMS OF A7 NACHR/PAM-MEDIATED NEUROPROTECTION AGAINST TAT NEUROTOXICITY; (2) TO DEFINE THE MECHANISMS OF A7 NACHR/PAM-MEDIATED INHIBITION OF HIV REPLICATION AND LATENT HIV REACTIVATION; AND (3) TO DETERMINE THE IN VIVO EFFECTS OF A7 NACHR/PAM ACTIVATION ON HIV NEUROPATHOGENESIS AND HIV REPLICATION AND LATENCY IN THE CNS AND PERIPHERY. WE WILL USE A COMBINED MOLECULAR, CELLULAR, BIOCHEMICAL, AND GENETIC APPROACH, INCLUDING THE USE OF PRIMARY MOUSE AND HUMAN CULTURES, ITAT MICE AND A7 NACHR KNOCKOUT MICE, THE INFECTIOUS AND REPLICATION-COMPETENT ECOHIV MODEL, AND SINGLE NUCLEUS ADVANCED GENOMICS TECHNOLOGIES. THE ANSWERS SOUGHT HAVE FUNDAMENTAL SIGNIFICANCE FOR OUR UNDERSTANDING OF NOT ONLY THIS CRITICAL AND PERVASIVE PROTEIN HIV TAT AND ITS ROLE IN HIV NEUROPATHOGENESIS BUT ALSO THE MOLECULAR MECHANISMS OF HIV TRANSCRIPTION INHIBITION BY A7 NACHR/PAM ACTIVATION. THE FINDINGS FROM THE PROPOSED STUDIES ARE EXPECTED TO PROVIDE MECHANISTIC AND PRE-CLINICAL EVIDENCE TO SUPPORT THE USE OF A7 NACHR PAM AS HAND THERAPEUTICS AND INFORM A NEW INTERVENTION STRATEGY FOR HIV NEUROPATHOGENESIS. THE ENORMOUS AMOUNT OF INFORMATION AVAILABLE ON HIV TAT, HIV INFECTION AND PATHOGENESIS OF THE CNS, AND THE ROLES OF A7 NACHR/PAM IN OTHER NEURODEGENERATIVE DISEASES, AND THE RESULTS OBTAINED FROM OUR RECENT STUDIES MAKE THE ACCOMPLISHMENT OF THESE AIMS PRACTICAL.