Pathogenic Linking of HIV Integrase Inhibitors, Folate Receptors, and Cerebral Folate Deficiency

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Abstract Current human immunodeficiency virus (HIV) antiretroviral therapy (ART) is effective at reducing viral loads, but treatment is frequently associated with significant side effects. Adverse events (AEs) reported with HIV ART include vascular, metabolic, and neurological adverse events (NAEs). Several studies support that folate and homocysteine (HCY) are common modifiers of HIV-associated vascular AEs and NAEs. Specifically, HIV- infected patients often have lower serum folate and elevated HCY. Additionally, HCY levels are reported to be higher in HIV-infected patients treated with ART compared to HIV-infected patients not exposed to ART. Folate and HCY are also reported to modify neural injury in HIV-infected individuals. A clinical study reported that the prevalence of folate deficiency is highest among HIV-infected neuropsychiatric patients; however, folate supplementation improved neuropsychiatric assessment scores as well as CD4 counts. We propose testing of integrase inhibitors (INIs): raltegravir, dolutegravir, elvitegravir, bictegravir, and cabotegravir, for impacts on cerebral folate concentrations and NAEs. We report that multiple INIs are partial antagonists against folate receptor (FOLR1). The FOLR1 protein is known to influence serum folate, HCY, and cerebral spinal fluid (CSF) folate concentrations. We hypothesize that serum folate and CSF folate concentrations are reduced by specific INIs and mechanistically due to, at least in part, FOLR1-folate antagonism. Furthermore, we expect that the INI- FOLR1 interactions observed in biochemical assays will produce cerebral folate deficiency in mouse models and neurotoxicity in human cellular studies. These data are also expected to support folate-based mitigation strategies to reduce ART-related NAEs in humans.