# Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $678,736

## Abstract

Injection drug use increases the probability of contracting HIV, and opioid use disorder (OUD) accelerates HIV-
1 infection through immune suppression and direct CNS actions. Glutamatergic excitotoxicity is a major factor
in HIV-dependent CNS injury, but emerging evidence also suggests a loss of inhibitory GABAergic function in
neuroHIV. The parallel loss of Cl− homeostasis and GABAergic tone will worsen excitatory outcomes since
‘disinhibition’ results in net excitation. If this is true, then interventions that protect inhibitory systems are
predicted to at least partially negate ‘excitotoxic’ effects of HIV. KCC2 is the main transporter responsible for
maintaining [Cl−]i homeostasis and GABAergic function in the adult CNS and is the focus of proposed studies.
Although the idea of disinhibition as a driving force is embraced for other neurological disorders (e.g., autism,
certain epilepsies, opioid dependence, traumatic brain/spinal cord injury), it represents a conceptual shift about
mechanisms underlying synaptodendritic dysfunction in neuroHIV. The Cl− concentration inside neurons ([Cl−]i)
is small and the Cl− reversal potential (ECl) is close to the resting membrane potential. Thus, minor changes in
[Cl−]i can greatly affect the strength and polarity of inhibitory (e.g., GABAA) transmission. NKCC1 (Cl− uptake)
and KCC2 (Cl− efflux) co-transporters are key regulators of [Cl−]i, and KCC2 expression/function is essential for
adult neuron survival. Their balance can be regulated by cytokines/trophic factors (e.g., BDNF) from glia,
therapeutically (CLP290), genetically, and by opioids. Importantly, we find that increasing KCC2 levels/function
strongly protects against exposure to Tat, gp120, infectious HIV, and opioids in human and mouse neurons. In
vivo, maintaining KCC2 phosphorylation can normalize KCC2 localization in Drd2-expressing striatal medium
spiny neuron (MSN) cell membranes and reverse motor deficits due to HIV-1 Tat. Aim 1 uses in vitro models
including iPSC MSNs, infective HIV, and optical electrophysiology to identify mechanisms by which HIV and/or
opioids alter [Cl−]i homeostasis, dysregulate D1/D2 MSN excitability, how this triggers synaptodendritic injury,
and protective strategies. Despite its fundamental importance, the role of KCC2 in excitatory/inhibitory (E-I)
imbalances and altered ECl and EGABA have never been explored in the context of HIV/OUD. Aim 2 extends the
studies in vivo/ex vivo. 2 transgenic models (Tat+/-, HIVTg26) that both mimic clinical pathology with considerable
fidelity are crossed with transgenic mice expressing Drd1a-tdTomato (D1) and Drd2-eGFP (D2) to identify both
striatal MSN populations. Acute (2 wk) and chronic (8 wk) HIV/Tat exposure times are examined; separate
cohorts of mice (both sexes) receive concurrent, ramping exposure to morphine (s.c.). Comprehensive studies
of [Cl−]i regulation in MSNs (gramicidin-perforated patch physiology), synaptodendritic injury, and behavior
related to striatal fu...

## Key facts

- **NIH application ID:** 10840348
- **Project number:** 5R01DA057346-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Kurt F Hauser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,736
- **Award type:** 5
- **Project period:** 2022-08-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840348

## Citation

> US National Institutes of Health, RePORTER application 10840348, Innovative therapeutic approaches to address excitotoxic CNS/neuronal damage in opioid-neuroHIV comorbidity (5R01DA057346-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10840348. Licensed CC0.

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