# Molecular Mechanisms of Increased Risk of Racial and Ethnic Minorities for HIV Associated Neurocognitive Disorders

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $50,520

## Abstract

Approximately 37 million people worldwide are living with HIV. HIV enters the CNS within 10 days of peripheral
infection, with development of HIV Associated Neurocognitive Disorders (HAND) in ~50% of infected people
despite ART. This is due to host/viral inflammatory and toxic factors within the CNS promoting neuronal injury.
Studies have shown increased risk and incidence of HIV infected Hispanics for HAND compared to Whites.
Molecular mechanisms underlying this increased risk have not been extensively studied. One mechanism by
which HIV enters the CNS is by transmigration of infected monocytes across the blood brain barrier (BBB),
establishing CNS HIV reservoirs, and inducing inflammation and neurotoxicity. A mature monocyte subset
expressing the LPS receptor, CD14, and FcγIII receptor, CD16, is key to HIV neuropathogenesis, increased in
the peripheral blood of HIV-infected people, and preferentially infected with HIV. We showed that CD14+CD16+
monocytes from HIV-infected people transmigrate preferentially across our human BBB model to CCL2 and
CXCL12, chemokines elevated in the CNS of HIV-infected people. We also showed that CD14+CD16+
monocytes from HIV-infected people with HAND transmigrate in greater numbers to CCL2 than those from
people with normal cognition. We showed that an antagonist to CXCR7, a recently identified CXCL12 receptor
on monocytes, blocks CXCL12-mediated transmigration of specifically CD14+CD16+ monocytes from HIV-
infected people, and we propose this as a therapeutic target to reduce their entry into the CNS. HIV DNA
copies/106 PBMC from HIV-infected people, specifically within CD14+CD16+ monocytes, correlate with HAND.
Using cultured CD14+CD16+ monocytes, we showed that monocytes harboring HIV (HIV+) preferentially
transmigrate across the BBB to CCL2 as compared to uninfected but HIV-exposed monocytes, and that this
selective advantage is due, in part, to increased junctional proteins JAM-A and ALCAM. However, there are no
studies addressing whether CXCL12-mediated transmigration of mature monocytes, nor whether CXCL12-
mediated transmigration specifically of HIV+CD14+CD16+ monocytes, correlate with HAND in Hispanics.
Monocytes contribute to peripheral immune activation in HIV-infected people. Once CD14+CD16+ monocytes
enter the CNS, they produce host/viral toxic factors that promote neuronal damage and HAND. We
hypothesize that: 1. In a select cohort of HIV-infected Hispanics on ART, Hispanics with HAND, compared to
those with normal cognition, have a higher percent of peripheral CD14+CD16+ monocytes expressing CCL2,
CXCL12, TNF-a, and/or IL-6, and have higher levels of these mediators; 2. CD14+CD16+ monocytes from this
cohort, particularly those harboring HIV, will preferentially transmigrate to CXCL12, and this will correlate with
HAND; 3. Preferential transmigration of HIV+ monocytes to CXCL12 will be blocked with antibodies to JAM-A
and ALCAM, and an inhibitor to CXCR7; 4. Hispanics with HAND will have higher HIV D...

## Key facts

- **NIH application ID:** 9974295
- **Project number:** 5F31MH116825-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Rosiris Leon Rivera
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-07-16 → 2021-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974295

## Citation

> US National Institutes of Health, RePORTER application 9974295, Molecular Mechanisms of Increased Risk of Racial and Ethnic Minorities for HIV Associated Neurocognitive Disorders (5F31MH116825-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974295. Licensed CC0.

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