# Impact of illicit drugs, HIV, and ART on neuroinflammation and BBB disruption

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $752,263

## Abstract

We propose is to examine molecular mechanisms of HIV-mediated inflammation in the presence of
antiretroviral therapy (ART) and drugs of abuse. Substance abuse often exacerbates neuroinlammation. We
will use methamphetamine (meth) as it has been shown to enhance HIV CNS disease, and dopamine as a
model for drug abuse as all substances of abuse increase CNS extracellular dopamine. HIV infection of the
CNS results in chronic inflammation that leads to cognitive deficits in more than 50% of infected people. This
inflammation and subsequent CNS damage is not mitigated with ART. Thus, triggering inflammation is a key
process in HIV disease and therapies to limit immune activation and neuroinflammation must be developed to
improve the quality of life of HIV infected people. HIV enters the CNS soon after peripheral infection and
despite ART, persists within infected cells. HIV entry into the brain is mediated, at least in part, by infected
monocyte transmigration across the blood brain barrier (BBB). A mature subset of monocytes that expresses
CD14 and CD16 is a key mediator of HIV CNS disease and is increased in number in the peripheral blood of
HIV infected people. These monocytes are productively infected with HIV and are primed to cross the BBB.
Within the CNS, HIV infected monocytes may differentiate into macrophages that can persist for years. This
leads to infection/activation of CNS cells, resulting in chronic neuroinflammation with the production of virus
and/or viral proteins, cytokines and chemokines. Chemokines, in particular CCL2, increase transmigration of
peripheral blood monocytes, continuing neuroinflammation. Thus, chronic inflammation is thought to mediate
neuronal damage in a large percentage of infected individuals by mechanisms not well understood. We will
characterize the effects of meth, HIV and tat, and ART on monocyte entry into the CNS and on subsequent
neuroinflammation. We will test potential therapeutics to limit inflammation and guide efficacy of ART. We
hypothesize that meth use combines with HIV infection to exacerbate neuroinflammation and compromise BBB
integrity, increasing transmigration of uninfected and HIV-infected monocytes into the brain, leading to
cognitive impairment. Based on our new preliminary data that tenofovir increases junctional proteins on the
BBB, we also hypothesize that certain ART regimens, especially in meth abusers, may negatively impact
cognitive function by synergizing with meth to increase BBB permeability and neuroinflammation. We will
characterize effects of meth, HIV and tat, and ART on cytokines, chemokines, and adhesion molecules
elaborated by and expressed on CD14+CD16+ monocytes that facilitate entry into the CNS, and in causing
BBB permeability and transmigration of CD14+CD16+ monocytes resulting in inflammation, and the impact of
ART. We will use a murine model to evaluate the in vivo impact of meth, HIV and its proteins, and ART on BBB
permeability and migration of inflammatory cell...

## Key facts

- **NIH application ID:** 10153747
- **Project number:** 5R01DA044584-06
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Joan Weinberger Berman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $752,263
- **Award type:** 5
- **Project period:** 2017-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153747

## Citation

> US National Institutes of Health, RePORTER application 10153747, Impact of illicit drugs, HIV, and ART on neuroinflammation and BBB disruption (5R01DA044584-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10153747. Licensed CC0.

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