# Single cell transcriptomic and epigenomic changes during chronic HIV infection and cocaine self-administration

> **NIH NIH U01** · ALLEN INSTITUTE · 2024 · $3,653,101

## Abstract

PROJECT SUMMARY
This application is submitted in response to RFA-D-21-019: Single Cell Opioid Responses in the Context of HIV
(SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, and/or Cocaine
Exposures. We have assembled an outstanding team of investigators with world-class expertise in HIV virology,
addiction neurobiology, and single cell transcriptomics. We will leverage state-of-the-art single-nuclei RNA
sequencing (snRNA-seq) coupled to single-nuclei epigenetics (snATAC-seq) to define the transcriptional and
epigenetic landscape of neuronal and nonneuronal cells in addiction-relevant brain cells of HIV-infected mice
that compulsively self-administer cocaine. In this manner we will identify cell types and brain sites in which HIV
and cocaine interact to exacerbate the negative impact of HIV infection on the brain and contribute to the
persistence of cocaine use disorder in infected individuals. To facilitate this goal, we have developed an extended
access intravenous cocaine self-administration procedure for mice that precipitates compulsive-like response for
cocaine that is resistant to negative outcome (contingently delivered noxious foot shocks). We will utilize EcoHIV,
which is a modified HIV strain that can infect conventional immunocompetent mice. The Chromium Single Cell
Multiome ATAC and Gene Expression assay and Multiplexed error-robust fluorescence in situ hybridization
(MERFISH) will be used to identify cocaine and/or HIV-responsive cells in the brain with unprecedented cellular
and spatial resolution. We will confirm our major findings using postmortem brain tissues from cocaine-
experienced HIV-infected individuals. Our goals will be accomplished through the following four specific aims. In
Aim 1, we will characterize compulsive-like cocaine intake in control and HIV-infected mice and determine the
impact of antiretroviral treatment (ART) on cocaine response in these mice. In Aim 2, we will use snRNA-seq
and Mulitome assays to identify those cells that show the most robust transcriptional and epigenetic plasticity to
cocaine consumption and HIV infection. In Aim 3, we will use MERFISH to confirm and validate our major snRNA-
seq and Multiome assay findings, and generate more refined spatially resolved maps of those cells most
impacted by cocaine and/or HIV. In Aim 4, we will confirm our major findings using post-mortem human brain
tissues. This highly innovative, collaborative and multidisciplinary program of research promises to yield
fundamental new insights into disease-related interactions between HIV infection and cocaine use.

## Key facts

- **NIH application ID:** 10819549
- **Project number:** 5U01DA056003-03
- **Recipient organization:** ALLEN INSTITUTE
- **Principal Investigator:** Paul J. Kenny
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $3,653,101
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819549

## Citation

> US National Institutes of Health, RePORTER application 10819549, Single cell transcriptomic and epigenomic changes during chronic HIV infection and cocaine self-administration (5U01DA056003-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10819549. Licensed CC0.

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