# Modeling CNS dynamics in HIV infection and cannabinoids with forebrain organoids

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $695,214

## Abstract

PROJECT SUMMARY
HIV-Associated Neurocognitive Disorder (HAND) persists in up to 50% of the HIV-positive population, often in
spite of low or undetectable viral loads due to effective antiretroviral therapy (ART). Microglia are the resident
macrophages in the central nervous system (CNS) and are thought to be a persistent reservoir of HIV in ART
treated patients. Microglia secrete a panoply of factors that impact neuronal function and these secreted
factors are altered during HIV infection of microglia. In addition to HIV virus-host interactions mediated by
microglia, many exogenous factors can modify these interactions or directly impact the CNS itself, making it
difficult to dissect the underlying causes of neural pathology leading to HAND. To establish a physiologically-
relevant platform to investigate the dynamics of HIV infection in the context of ART and other co-factors, we
will use human induced pluripotent stem cells to generate human microglia that we can co-culture with our
well-characterized 3D model of the developing cerebral cortex. This integrated 3D cerebral organoid model will
recapitulate many of the critical cell populations thought to contribute to HAND-related pathology including
glutamatergic neurons, astrocytes, and microglia. We will evaluate the efficacy of the cerebral organoids to
model HIV infections by measuring HIV replication kinetics and suppression, as well as HIV protein expression
in different cell types (Aim 1). We will then measure the impact of HIV on neuronal development and function at
several time points following acute exposure (Aim 2). We will perform morphological and electrophysiological
analyses and RNA sequencing at both the single cell and population level to determine the cell type-specific
transcriptional responses to HIV exposure. Finally, we will evaluate the impact of exogenous drugs on these
measures of viral replication and neuronal function (Aim 3). As a proof-of-concept, we will test a preferred
regimen of ART, as well as cannabinoids, both with and without HIV exposure to begin to dissect the impact of
these common co-factors on cellular properties that may contribute to pathology underlying HAND. Successful
completion of these experiments will result in a validated platform to model the dynamics of neuroinflammatory
disorders using brain region-specific cerebral organoids integrated with human microglia.

## Key facts

- **NIH application ID:** 10197084
- **Project number:** 5R01DA049514-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kimberly Christian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $695,214
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197084

## Citation

> US National Institutes of Health, RePORTER application 10197084, Modeling CNS dynamics in HIV infection and cannabinoids with forebrain organoids (5R01DA049514-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10197084. Licensed CC0.

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