Project Grant F31HL186719

ROLE OF THE DUFFY ANTIGEN RECEPTOR FOR CHEMOKINES IN VASCULAR DYSFUNCTION AND HYPERTENSION IN THE CONTEXT OF HIV - PROJECT SUMMARY COMBINATION ANTIRETROVIRAL THERAPY (CART) HAS TRANSFORMED HIV INTO A MANAGEABLE CHRONIC DISEASE. HOWEVER, PEOPLE LIVING WITH HIV (PLWH) REMAIN AT AN INCREASED RISK FOR CARDIOVASCULAR DISEASE (CVD), PARTICULARLY HYPERTENSION, EVEN WITH EFFECTIVE VIRAL SUPPRESSION. HIV VIRAL PROTEINS PERSIST IN CIRCULATION DESPITE CART AND WELL-CONTROLLED VIREMIA AND HAVE BEEN SHOWN TO CONTRIBUTE TO CVD. FURTHERMORE, CVD RISK IS DISPROPORTIONATELY HIGH AMONG INDIVIDUALS OF AFRICAN ANCESTRY, MANY OF WHOM HARBOR A MUTATION IN THE DUFFY ANTIGEN RECEPTOR FOR CHEMOKINES (DARC-NULL GENOTYPE). DARC IS AN ATYPICAL CHEMOKINE RECEPTOR EXPRESSED ON RED BLOOD CELLS (RBC) AND VENULAR ENDOTHELIAL CELLS, WHERE IT REGULATES INFLAMMATION BY SEQUESTERING CHEMOKINES. LOSS OF DARC DISRUPTS CHEMOKINE HOMEOSTASIS AND PROMOTES INFLAMMATION. TO INVESTIGATE HOW LOSS OF DARC INFLUENCES VASCULAR INJURY, WE USED THE DARC-/-, WHICH REPLICATES THE DARC NULL GENOTYPE COMMON IN THIS POPULATION, AND A NOVEL TG26DARC-/- MOUSE MODEL EXPRESSING HIV PROTEINS ON A DARC-DEFICIENT BACKGROUND TO INVESTIGATE THE COMBINED ROLES OF DARC DEFICIENCY AND HIV PROTEIN EXPOSURE. OUR PRELIMINARY DATA SHOW THAT DARC DEFICIENCY INCREASES SYSTOLIC BLOOD PRESSURE (SBP) AND IMPAIRS VASCULAR FUNCTION, WITH NO FURTHER IMPAIRMENT IN THE TG26DARC-/- MICE, SUGGESTING THAT LOSS OF DARC AND HIV PROTEINS DRIVE HYPERTENSION THROUGH DISTINCT AND NON- SYNERGISTIC MECHANISMS. CYTOKINE PROFILING REVEALED A MECHANISTIC DIVERGENCE IN DARC-/- MICE WITH ELEVATED PLASMA IL-6, IL-1B, TNFA, AND IL-17A, AND REDUCED IL-1A AND ENDOTHELIAL NOX1 EXPRESSION, SHIFTING THE INFLAMMATORY PROFILE TOWARD AN IL-17-DOMINANT STATE. THESE FINDINGS SUGGEST THAT DARC DEFICIENCY IMPAIRS ENDOTHELIAL FUNCTION AND ELEVATES SBP THROUGH HIGH CIRCULATING CYTOKINE LEVELS BUT ALSO SHIFTS THE INFLAMMATORY MILIEU AWAY FROM IL-1A AND POTENTIALLY TOWARD AN IL-17-DOMINANT PROFILE IN THE PRESENCE OF HIV PROTEINS. THIS PROPOSAL WILL TEST THE HYPOTHESIS THAT DARC REGULATES BLOOD PRESSURE BY MODULATING CIRCULATING IL-17A AND IL- 1A LEVELS. AIM 1 WILL TEST WHETHER DARC DEFICIENCY PROMOTES IL-17A-MEDIATED VASCULAR INFLAMMATION AND USE BONE MARROW TRANSPLANTATION TO DEFINE THE RELATIVE CONTRIBUTION OF RBC VS ENDOTHELIAL EXPRESSED DARC. AIM 2 WILL INVESTIGATE HOW DARC REGULATES IL-1A PRODUCTION IN CD4 T CELLS. TOGETHER, THESE PROPOSED AIMS WILL DEFINE THE MECHANISM BY WHICH A COMMON AFRICAN ANCESTRY-LINKED POLYMORPHISM DRIVES ENDOTHELIAL DYSFUNCTION AND HYPERTENSION IN THE CONTEXT OF HIV. THE PROJECT WILL BE CONDUCTED UNDER THE MENTORSHIP OF DRS. ERIC BELIN DE CHANTEMELE AND NEAL WEINTRAUB AT THE VASCULAR BIOLOGY CENTER, AUGUSTA UNIVERSITY, WHICH HAS A STRONG TRACK RECORD OF TRAINING SUCCESSFUL PRE- AND POST-DOCTORAL FELLOWS. THE PROPOSED PROJECT IS FOR 3 YEARS OF FUNDING, CULMINATING WITH A DISSERTATION DEFENSE AT THE END OF THE THIRD YEAR. FINDINGS FROM THIS WORK WILL UNCOVER A NOVEL MECHANISM LINKING DARC TO T CELL-MEDIATED VASCULAR INJURY AND OFFER MECHANISTIC INSIGHT INTO RACIAL DISPARITIES IN HIV-ASSOCIATED CVD.