# Prevention of HIV and drug abuse-induced brain pathology by targeting mitochondria

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $404,557

## Abstract

Abstract
Drugs of abuse, such as methamphetamine (METH), can work in concert with specific anti-
retroviral therapeutics and residual viral replication in HIV-infected brain, to drive the HIV-related
brain pathology and neurocognitive dysfunction. The central hypothesis of this proposal is
that HIV brain life cycle is influenced by exposure to METH, which facilitates the entry of
HIV into the brain, establishing infection and latency, and, along with specific anti-
retroviral drugs, contribute to neuroimmune activation and neuroinflammatory reactions.
We will evaluate these events by focusing on novel and previously unexplored aspects of HIV
biology at the blood-brain barrier (BBB). Based on our preliminary data, we propose that toll-like
receptors 2 and 4 (TLR2/4) are critical players of cerebrovascular toxicity of METH, leading to
dissembling of TJ protein complexes and facilitated HIV entry into the brain (Aim 1). We will next
evaluate the mechanisms of METH-induced enhanced HIV replication and establishment of latent
infection in BBB pericytes (Aim 2). Our pioneering findings indicated that BBB pericytes are
permissive to HIV infection. In the current proposal, we will continue this novel research by focusing on
the role of METH in active and latent infection in these cells. Because METH, HIV, and anti-retroviral
drugs share mitochondrial dysfunction as one of the primary mechanisms of their cerebrovascular
toxicity, an important part of the proposal will be devoted to exploring novel nanotechnologies
aimed to target mitochondria for therapeutic protection (Aim 3). Thus, we will provide innovative
therapeutic strategies to protect against cerebrovascular toxicity and neuroimmune activation,
which are driven by METH and specific anti-retroviral drugs in HIV-infected brain.
The proposed research is not only highly innovative, but it is likely to lead to the development of
new translational knowledge for the clinic. This application will study novel and previously
unrecognized mechanisms and pathogenesis underlying the development of brain infection by
HIV, in the context of drug abuse and anti-retroviral strategies. With expertise in drug abuse
research, BBB biology, HIV infection, and mitochondria targeting, we are uniquely positioned to
perform the proposed, highly innovative project.

## Key facts

- **NIH application ID:** 10158459
- **Project number:** 5R01DA044579-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Michal Toborek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,557
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158459

## Citation

> US National Institutes of Health, RePORTER application 10158459, Prevention of HIV and drug abuse-induced brain pathology by targeting mitochondria (5R01DA044579-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10158459. Licensed CC0.

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