# Modeling drugs of abuse-HIV interactions using iPSC-derived human cerebral organoids

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $871,147

## Abstract

Summary
HIV-infected microglia release cytokines, chemokines and viral gene products, such as gp120 and tat, that
are toxic to neurons. In this proposal, we will use human induced pluripotent stem cells (iPSCs) to generate
cortical and dopaminergic neurons as well as microglia, which will be cultured as organoids to model HIV-drug
abuse interactions in conjunction with in-depth genomic approaches and electrophysiology. We show
electrophysiological results that demonstrate that the levels of differentiation of the neurons in our organoids
are comparable to in vivo and ex vivo preparations and are among the best that can be found in the scientific
literature. To identify candidate host regulators of HIV expression and mediators of HIV-induced tissue damage
and disease progression, we will expose microglia-containing cerebral organoids to methamphetamine
(METH), a stimulant, and morphine, an opiate, which are members of two of the classes of drugs of abuse that
are more prevalent among People Living with HIV/AIDS (PLWHA). Cerebral organoids will be exposed to toxic
HIV products such as Tat, gp120, drugs of abuse and combination antiretroviral therapy (cART). In some
experiments we will also incorporate iPSC-derived astrocytes into microglia-containing cerebral organoids to
test the role of astrocytes in neuroprotection and neurodegeneration. We will carry out single-cell gene
expression profiling of iPSC-derived organoids exposed to drugs of abuse, HIV products, and cART and we
will employ an advanced systems biology strategy to generate testable mechanistic hypotheses on the
pathogenesis of neurodegeneration and tissue damage in neuroHIV (Aim 1) and identify candidate regulators
of the LTR promoter that may shed light on the regulation of latency and reactivation of the HIV provirus (Aim
2). In preliminary studies, this computational experimental approach allowed us to identify candidate drivers of
gene expression changes associated with neuroHIV and neurodegenerative diseases, including Alzheimer’s
disease and drug and alcohol abuse. These findings support the overarching hypothesis that dissection of the
gene regulatory network of the central nervous system will pave the way for the identification of novel
mechanistic hypotheses and druggable targets to improve neuropsychological functioning of PLWHA and
substance abuse comorbidity.

## Key facts

- **NIH application ID:** 10246053
- **Project number:** 1R01DA053801-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Vez REPUNTE-CANONIGO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $871,147
- **Award type:** 1
- **Project period:** 2021-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246053

## Citation

> US National Institutes of Health, RePORTER application 10246053, Modeling drugs of abuse-HIV interactions using iPSC-derived human cerebral organoids (1R01DA053801-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246053. Licensed CC0.

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