# Antiretroviral Therapy and Neuroinflammation in the CNS

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $526,864

## Abstract

PROJECT SUMMARY
 Highly active anti-retroviral therapy (ART; HAART) has had tremendous success in suppressing HIV
replication and reducing HIV-associated morbidity and mortality. However, the prevalence of HIV-associated
neurological disorders (NeuroAIDS) such as neuropathic pain and neurocognitive deficits remain high, even in
the post ART era. This is puzzling in the perspective of low viral loads, and presents major clinical challenges.
Yet, the underlying neuropathophysiological mechanism is poorly understood. Emerging evidence suggests a
key role of ongoing chronic neuroinflammation in NeuroAIDS pathogenesis. Current mechanistic investigation
focuses on HIV-1 toxic proteins such as gp120 and Tat in eliciting neuroinflammation. However, given the low
viral loads after ART, the pathogenic significance of the proteins remains uncertain. Since HIV patients need to
stay on ART for a long time, we reason that it is clinically important to test the alternative possibility: anti-
retroviral therapy itself evokes neuroinflammatory responses, even though it controls HIV viral loads at a low
level and suppresses virus-induced immune responses. This hypothesized therapy-induced chronic
neuroinflammation, if validated, may have a profound impact on the design of future ART regimens. In this
study, we will focus on the potential involvement of drugs in the current ART, especially its backbone
components - nucleoside reverse transcriptase inhibitors (NRTIs). Based on extensive preliminary data, we
hypothesize that NRTIs critically contribute to the chronic neuroinflammation through a mechanism that
involves Wnt5a up-regulation. Specifically, our hypothesis entails that NRTIs cause Wnt5a increase in the
CNS, which then stimulates astrocytes to express pro-inflammatory factors. Chronic increase of the
inflammatory mediators is expected to cause NeuroAIDS-related neuronal damage. To test this hypothesis, we
will characterize NRTI-induced neuroinflammation in the CNS (Aim 1), elucidate the mechanism of NRTI-
induced CNS neuroinflammation (Aim 2), and determine the pathophysiological role of NRTI-induced CNS
neuroinflammation in pathological pain development (Aim 3). Successful completion of these conceptually
innovative studies will significantly advance our understanding of the neuropathogenic mechanisms by which
NRTIs/ART may contribute to neurological disorders in HIV patients. The new findings may lead to further
optimization of ART in clinical settings and the development of ART adjuvants to prevent NeuroAIDS, such as
chronic pain and cognitive deficits.

## Key facts

- **NIH application ID:** 9994409
- **Project number:** 5R01NS095747-05
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** JIN M CHUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $526,864
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994409

## Citation

> US National Institutes of Health, RePORTER application 9994409, Antiretroviral Therapy and Neuroinflammation in the CNS (5R01NS095747-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9994409. Licensed CC0.

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