HIV and cocaine mediated lipid dysregulation in microglia: Immunometabolism mechanisms underlying NeuroHIV - Abstract In the era of combination antiretroviral therapy, people living with HIV (PLWH) have a similar life-expectancy to the HIV-negative population. However, the life-quality of PLWHIV is still deeply compromised due to the prevalence of neurological symptoms (NeuroHIV). Recently, a novel subtype of Mg, called lipid-droplet- accumulating Mg (LDAM), has been identified in both mouse and human aging brains as well as in Alzheimer’s disease. LDAM have dysregulated lipid metabolism and are characterized by increased reactive oxygen species (ROS) production, low levels of inflammation, and defective phagocytosis. Previous investigations have shown that HIV infection and abused drugs could affect brain lipid metabolism which contributes to NeuroAIDS. However, whether and how HIV/HIV proteins and abused drugs affect microglial lipid metabolism and whether and how LDAM are involved in NeuroHIV in the context of HIV and abused drugs have never been explored. We initiated an investigation and obtained these preliminary data : (1) HIV-TAT and cocaine individually increases lipid droplets (LDs) formation in vitro and in vivo; (2) HIV-TAT and cocaine individually upregulates the activity of sterol regulatory element binding proteins (SREBPs) - mediated pathway in time- and dose- dependent manners in vitro; (3) SREBP2 inhibitor 5-O-methylembelin blocks HIV-TAT-mediated LDs formation and Mg activation; (4) The co-exposure of cocaine and HIV-TAT exerts combined effects on Mg lipid metabolism in vitro and in vivo; (5) HIV-inducible(i) TAT mice both show increased LDAM in the brains compared to age-matched counterparts; (6) SIV (+) macaque brains showed increased LDAM compared to their age-matched uninfected counterparts. Based on these preliminary data and the critical roles of LDAM in multiple neurodegenerative diseases, we hypothesize that dysregulated lipid metabolism serves as the master mechanism responsible for Mg activation in the context of HIV/HIV proteins and cocaine, and that targeting on LDAM could mitigate NeuroHIV in PLWH who use cocaine. We will test this hypothesis in the following two specific aims (SA) through complimentary in vitro and in vivo approaches: SA1: Determine the role of dysregulated lipid metabolism in Mg activation and neuronal injuries in the context of HIV-TAT/HIV and cocaine in vitro. SA2: Determine the potential therapeutic effects of inhibiting lipid metabolism on NeuroHIV symptoms. We will correlate lipid dysregulation and Mg activation with neurological behaviors to validate the therapeutic effects of targeting lipid metabolism on NeuroHIV in PLWH using cocaine.
