# Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $736,183

## Abstract

PROJECT ABSTRACT
HIV-1 associated neuroinflammation and neurotoxicity lead to cognitive impairments (HIV-1-associated
neurocognitive disorders or HAND) even in those under suppressive antiretroviral therapy (ART). As people
living with HIV-1 age, a compounding effect is occurring, with age associated dementia added to HAND,
leading to a complex web of neurocognitive deficit. This will have tremendous implications for health care
systems not only in the USA but also in the developing world. How HAND develops, and how it could be
modified remain mysterious, largely because It has been very difficult to study HIV-1 infection and HAND in the
human brain. Over the past few years new developments in stem cell technologies have permitted the
differentiation of “cerebral organoids” from induced pluripotent stem cells (iPSCs), and these cultures can be
grown in vitro in conditions that promote three-dimensional expansion of neuroectoderm, in cerebral organoid
or “miniature brain” forms. Cerebral organoids are heterogeneous and form a variety of brain regions, including
ventral forebrain, cerebral cortex, hippocampus, and mid- and hindbrain boundary. They exhibit neurons that
are functional and capable of electrical excitation, and develop microglia. These brain organoids also resemble
human cortical development at the gene expression level, and allow in depth analysis of neural networks, cell
behavior, drug screening, disease modeling, and variations in brain development. While brain-region
composition varies in organoids from different iPSC lines, regional gene-expression patterns remain largely
reproducible across individuals. These create unparalleled new opportunities to study HIV-1 infection of the
brain. We propose to develop our iPSC derived organoid model which incorporates microglia, into one that
better represents an adult mature brain that can support robust HIV-1 infection. With this model, we can test
whether different viruses lead to differential neurotoxicity and if cells other than microglia can be latently
infected with virus. We will test how individual proteins from the virus, including HIV-1 Tat causes neurological
damage, and how ART or drugs such as Didehydro-Cortistatin A (dCA), which cross-neutralizes Tat activity,
affects the process. Interestingly, exposure to Tat also potentiates cocaine-mediated reward mechanisms,
which further promotes HAND, revealing a complex web of interactions between HIV-1 infection and drugs of
substance abuse. We will determine how Tat and cocaine collaborate in neurological damage and determine if
dCA can reverse it. As cerebral organoids provide a model for HIV-1 latency in the brain we can test whether
administration of dCA, can “block-and-lock” any residual virus, and finally whether HIV-1 specific cytotoxic T
cells (CTL) can eliminate virus in the organoid. Together, these studies promise to provide novel insights into
the pathogenesis of HAND, Tat mediated neurotoxicity, effects of cocaine, and th...

## Key facts

- **NIH application ID:** 10398244
- **Project number:** 5R01DA052027-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** DOUGLAS F NIXON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $736,183
- **Award type:** 5
- **Project period:** 2020-07-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10398244

## Citation

> US National Institutes of Health, RePORTER application 10398244, Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment (5R01DA052027-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10398244. Licensed CC0.

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