# Role of chemokines in neuronal function and survival

> **NIH NIH R37** · DREXEL UNIVERSITY · 2024 · $483,268

## Abstract

SUMMARY OF PROPOSAL
Modern antiretroviral therapies have transformed Human Immunodeficiency Virus (HIV) infection into a 
chronically manageable disease. However, a significant amount of people with HIV on antiretroviral therapies 
present with a spectrum of neurological symptoms. These HIV-associated neurocognitive disorders (HAND) 
remain an important aspect of modern HIV pathology, prognosis, and clinical management, raising the need 
for the discovery of adjuvant therapies. Clinical evidence also suggests that HAND can be aggravated by 
substance abuse, including opioids, which is highly prevalent in people with HIV. Understanding how opioid 
use contributes to cognitive impairment in HAND will help identify new approaches and drug targets to treat 
HAND in opioid users.
For the past two decades, we have investigated how HIV neurotoxins and opioids contribute to HAND by 
regulating the chemokine receptor CXCR4 in the central nervous system. We have demonstrated that proper 
CXCR4 signaling via its natural ligand (the chemokine CXCL12) is not only neuroprotective, but it can also 
rescue structural (i.e. dendritic spines loss) and functional (i.e. cognitive flexibility) deficits in an animal model 
of HAND. Further, we discovered that this pathway is hijacked by viral proteins and inhibited by µ-opioid 
receptor agonists, which revealed a new mechanism whereby opioid use can aggravate HAND. Overall, our 
body of work demonstrates that the CXCL12/CXCR4 axis is tightly integrated into homeostatic and plasticity 
processes in cortical neurons, and disruption of CXCR4 signaling via HIV proteins, inflammatory mediators, 
and opioids is an important component of HAND.
For the next (and last) period of this award, we plan 
to capitalize on this knowledge and other recent 
findings and fill key gaps in the field that will help us 
assess the therapeutic value of these discoveries. 
Thanks to new collaborations, we shifted our focus 
from molecular mechanisms to network level 
function – with a main interest in the role of cortical 
interneurons in HAND. Notably, cortical 
interneurons dysfunction has emerged as a key 
factor in neuropsychiatric conditions linked to 
substance use disorders.
Our objectives for the next five years are to determine how interneurons contribute to CXCL12’s regulation of 
neuronal network activity and cognition in models of HAND, and if the chemokine’s effects are inhibited by 
morphine via local circuit modulation. Studies in Aim 1 will examine synaptic plasticity deficits that are 
indicative of microcircuit dysfunction in the medial PFC of WT and HIV-tg rats, and if these network-level 
deficits are reversed by CXCL12 treatment. Aim 2 studies will examine how dendritic-targeting cortical 
interneurons that express CXCR4 (namely, SST+ inhibitory neurons) modulate the activity of local networks 
to enhance neuronal connectivity, and how these processes are affected by inhibitory neurons that express 
µ-opioid receptors. In...

## Key facts

- **NIH application ID:** 10819211
- **Project number:** 5R37DA015014-22
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Olimpia Meucci
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $483,268
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819211

## Citation

> US National Institutes of Health, RePORTER application 10819211, Role of chemokines in neuronal function and survival (5R37DA015014-22). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10819211. Licensed CC0.

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