# Defining the impact of drug use on immune function and fitness against HIV-1

> **NIH NIH DP1** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $1,176,000

## Abstract

PAR-20-221: NIDA Avant-Garde - Abstract Alex K. Shalek
ABSTRACT
HIV-1 prevention and cure strategies are urgently needed for people who inject drugs (PWID) with opioid use
disorder (OUD) or polysubstance used disorder (PSUD) given substantial risk for, and incidence of, HIV-1 and
others infection. Most prophylactic and therapeutic strategies under development for HIV-1 and other infections
rely on modulating host immunity. Nevertheless, we do not have a working knowledge of how opioids—which,
themselves, are immunomodulatory—and the lived experiences of those with OUD or PSUD (inclusive of
exposure to contaminated equipment, community infections, and physical and social environmental factors) alter
immune function in the absence or presence of HIV-1 infection and, thus, the efficacy of interventions against
HIV-1 and other pathogens. We hypothesize that opioids and OUD/PSUD modulate baseline immune responses
in the host (“function”), as well as immunity against other pathogens (“fitness”), impacting prevention and cure
strategies. Here, we propose a pioneering program to define, at unprecedented resolution, the cellular and
molecular impact of OUD and PSUD on immune function and response to pathogens, such as HIV-1. We will
also develop and utilize an innovative “compressed’ screening platform to functionally test, in high-throughput,
informed chemical and biological perturbations for prevention and cure strategies. More specifically, we will
deploy—and, where necessary, develop—cutting-edge single-cell and bulk genomic profiling methods to
generate functional hypotheses on how OUD and PSUD alter critical physiology associated with drug metabolism
(liver), innate mucosal defense (gastrointestinal tract (GI)), and adaptive immune function in tissues of relevance
to HIV-1 (liver, GI, and peripheral blood mononuclear cells (PBMCS)). We will explicitly characterize and contrast
changes in the presence and absence of HIV-1 infection. To systematically test resulting hypotheses, we will
create and implement “compressed” perturbation screens to examine simultaneously the individual impact of
multiple chemical and biological perturbations on limited primary samples (e.g., PBMCs, tissue biopsies). This
will enable us to delineate how factors associated with several aspects of OUD and PSUD intersect with HIV-1
infection. Given my lab’s broad and yet deep interdisciplinary expertise in developing and applying innovative
experimental and computational technologies to obtain mechanistic insights into the cellular and molecular
drivers of human health and disease, and our team of committed clinical collaborators in Boston and beyond,
we are uniquely positioned to successfully execute this pioneering, transformative investigation of the impact of
OUD and PSUD on immune function. Overall, our work will define the immunological landscape of OUD and
PSUD, and inform strategies to improve baseline immunity and the efficacy of preventions and cures against
HIV-1 and...

## Key facts

- **NIH application ID:** 10832602
- **Project number:** 5DP1DA053731-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Alex K Shalek
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,176,000
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832602

## Citation

> US National Institutes of Health, RePORTER application 10832602, Defining the impact of drug use on immune function and fitness against HIV-1 (5DP1DA053731-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10832602. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*