HIV and ART Disruptions in Glial Cell Lipid Metabolism and its Effect on Adolescent Myelination

PROJECT SUMMARY/ABSTRACT Human immunodeficiency virus (HIV) infections are dramatically climbing in adolescents, who are infected during a time of critical brain development characterized by significant myelination. Adolescents may therefore be particularly vulnerable to the white matter pathologies closely linked to HIV-associated neurocognitive disorders (HAND), which affect 30-50% of people living with HIV. Understanding the mechanisms resulting in HIV-related white matter deficits will be key in the development of therapies to promote myelin integrity and repair, which may greatly improve neurological function. One important factor predictive of both cognitive decline in HIV and a lack of myelin is altered brain lipid metabolism. Myelin is highly enriched in cholesterol and lipids, and both oligodendrocytes, the myelin-producing glial cells of the central nervous system, and astrocytes must synthesize large quantities of cholesterol and lipids for successful myelination to occur. Based on published and preliminary data, I hypothesize that glial lipid biosynthesis and transport essential for adolescent myelination are dysregulated by HIV or DTG/TDF/FTC antiretroviral therapy (ART), making lipid metabolism a potential therapeutic target for improving white matter integrity in adolescents living with HIV. To address this hypothesis, I will determine how HIV and ART affect 1) oligodendroglial lipid metabolism and resulting myelin lipid composition and adolescent myelination, and 2) astroglial lipid metabolism and release and its impact on myelin formation. Successful completion of the proposed aims will reveal whether HIV or ART affect lipid metabolism in either oligodendrocytes and/or astrocytes and whether this is detrimental to adolescent myelination. Results from the proposed studies will directly advance the mission of the NIMH by transforming our understanding of mechanisms of white matter pathology in adolescent HIV/HAND, revealing potential therapeutic targets for prevention of and recovery from HIV-related neuropathology.