# Immune Network Dysregulation of the Central Nervous System with HIV Persistence and Opioid Abuse

> **NIH NIH DP2** · YALE UNIVERSITY · 2022 · $2,512,500

## Abstract

PROJECT SUMMARY/ABSTRACT
HIV persists within the body despite successful suppression of viral replication with antiretroviral therapy (ART),
preventing eradication of the virus. Even a low level of persistent HIV in the brain may cause neurological
damage, as 30-50% of well-suppressed HIV individuals under ART develop HIV-associated neurocognitive
disorders (HAND). These abnormalities in the CNS are further complicated by opioid abuse, as opioid exposure
results in exaggerated neuroinflammation. CNS immune activation induced by HIV and OUD is incompletely
understood at the cellular level. Understanding the cellular basis for persistent CNS immune activation is critical
for reducing neurological morbidities in the growing population of adults with HIV and OUD. Recent advances in
massively parallel single cell RNA sequencing have uncovered numerous neuronal and glial populations widely
across the central nervous system in health and disease. Such methods provide a powerful and unbiased way
for understanding the organization of the cellular and immune network of the CNS based on transcriptional
profiles at the single cell level. Here, we propose to employ state-of-the-art and novel methodologies in
neuroscience, immunobiology, and computational biology to dissect the dysregulated immune network in the
CNS of patients with HIV and OUD and the cell-type-specific response to opioid in the context of HIV. We will
apply state-of-the-art single cell transcriptome analysis to uncover the molecular architecture and immune
activation of the CSF in the patients with HIV and OUD. We will leverage our large dataset of human brain single
nucleus RNA sequencing generated at the NIDA-supported CNS data generation center of Single Cell Opioid
Responses in the Context of HIV at Yale (Y-SCORCH) to characterize the alterations of neuroimmune
communications in OUD and HIV. We will develop and employ novel modern cell-type-specific approaches, such
as ex vivo culture system, to determine the opioid responses of brain immune cell types, including microglia and
brain-resident T cells, in the context of HIV. Determining the regulatory networks and molecular mechanisms of
HIV persistence in response to opioid exposure will greatly advance our understanding of HIV latency and may
provide novel insights and numerous pharmaceutical targets for treating HAND and eradicating HIV virus in HIV
persistent individuals with opioid use disorder.

## Key facts

- **NIH application ID:** 10469837
- **Project number:** 1DP2DA056169-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Le Zhang
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,512,500
- **Award type:** 1
- **Project period:** 2022-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469837

## Citation

> US National Institutes of Health, RePORTER application 10469837, Immune Network Dysregulation of the Central Nervous System with HIV Persistence and Opioid Abuse (1DP2DA056169-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10469837. Licensed CC0.

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