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

> **NIH NIH R21** · BAYLOR COLLEGE OF MEDICINE · 2020 · $200,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10023284
- **Project number:** 5R21MH122252-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Robert M Cabrera
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2019-09-24 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023284

## Citation

> US National Institutes of Health, RePORTER application 10023284, Pathogenic Linking of HIV Integrase Inhibitors, Folate Receptors, and Cerebral Folate Deficiency (5R21MH122252-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10023284. Licensed CC0.

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