Project Grant R01DA060753

EPIGENETIC REGULATION OF ASTROCYTE-SPECIFIC NLRP6 INFLAMMASOME AND PANOPTOSIS IN HIV TAT AND METHAMPHETAMINE-MEDIATED NEUROINFLAMMATION - PROJECT SUMMARY: ACCORDING TO THE CENTERS FOR DISEASE CONTROL AND PREVENTION, HIV INFECTION AND DRUG ABUSE ARE INTERTWINED EPIDEMICS THAT LIMIT ADHERENCE TO COMBINATION ANTIRETROVIRAL THERAPY (CART) AND CONTRIBUTE TO THE WORSENING OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS REFERRED TO AS "NEUROHIV." DESPITE THE ABILITY OF CART TO SIGNIFICANTLY DECREASE VIREMIA, THE BRAIN REMAINS A RESERVOIR OF LOW-LEVEL HIV REPLICATION WITH THE ACCUMULATION AND PERSISTENCE OF CYTOTOXIC VIRAL PROTEINS, INCLUDING THE HIV TRANSACTIVATOR OF TRANSCRIPTION (TAT). METHAMPHETAMINE IS A HIGHLY ADDICTIVE SYNTHETIC STIMULANT COMMONLY ABUSED BY HIV-INFECTED PEOPLE WORLDWIDE. IT IS GENERALLY ESTABLISHED THAT HIV/HIV PROTEINS AND METHAMPHETAMINE ACTIVATE INFLAMMASOMES IN CENTRAL NERVOUS SYSTEM CELLS, PARTICULARLY MICROGLIA. HOWEVER, THERE IS A KNOWLEDGE GAP IN OUR UNDERSTANDING OF HOW HIV/HIV PROTEINS AND METHAMPHETAMINE CONTRIBUTE TO ACTIVATING ASTROCYTE-SPECIFIC INFLAMMASOMES - NLRP6, LEADING TO NEUROINFLAMMATION, WHICH IS THE FOCUS OF THIS STUDY. THE LONG-TERM GOAL IS TO IDENTIFY THE MOLECULAR MECHANISM(S) INVOLVED IN HIV AND METHAMPHETAMINE-MEDIATED ASTROCYTE ACTIVATION, WHICH CAN SET THE STAGE FOR DEVELOPING NOVEL THERAPEUTIC TARGETS TO ALLEVIATE NEUROINFLAMMATION ASSOCIATED WITH NEUROHIV. THIS PROPOSAL USES IN VITRO, EX VIVO, AND IN VIVO APPROACHES TO IDENTIFY THE MOLECULAR MECHANISM(S) INVOLVED IN HIV TAT AND METHAMPHETAMINE-MEDIATED ASTROCYTE-SPECIFIC NLRP6 INFLAMMASOME AND ITS ROLE IN PANOPTOSIS-MEDIATED NEUROINFLAMMATION. THE CENTRAL HYPOTHESIS IS THAT HIV TAT-MEDIATED ASTROCYTE ACTIVATION AND NEUROINFLAMMATION IN NEUROHIV INVOLVE ZBP1/NLRP6-MEDIATED PANOPTOSIS. THE HYPOTHESIS WILL BE TESTED WITH TWO SPECIFIC AIMS, AND THE OUTCOME OF THIS STUDY WILL SET THE STAGE FOR DEVELOPING NOVEL THERAPEUTICS TO DAMPEN HIV AND DRUG ABUSE- MEDIATED NEUROINFLAMMATION IN NEUROHIV. OVERALL, THIS R01 APPLICATION AIMS TO DETERMINE HOW EXPOSURE TO HIV TAT AND METHAMPHETAMINE INDUCES THE ASTROCYTE-SPECIFIC INFLAMMASOME, NLRP6, AND ITS ROLE IN PANOPTOSIS- MEDIATED NEUROINFLAMMATION USING IN VITRO, EX VIVO, AND IN VIVO APPROACHES.