# Modeling HIV-1 Neuropathogenesis and neuronal dysregulation using 3D-organoids containing multiple CNS cell lineages

> **NIH NIH R56** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $686,284

## Abstract

Project Summary
HIV-associated neurocognitive disorder (HAND) range from mild to severe deficits in cognition and occurs in
more than 60% of HIV-1 subjects receiving combined antiretroviral therapy (cART). Pathological evaluation of
the frontal cortex of HIV-1 positive subjects revealed neuroinflammation with presence of HIV-1 infected
microglia/macrophages, astrogliosis, dendrites loss and synaptic pruning in neurons. The degradation of
dendrites that accompany these neuronal changes leads to synaptic loss, neuronal and cognitive decline, and
this causes development of HAND in people living with HIV. Moreover, these effects may be exacerbated by
illicit drug use abuse such as opioids, a drug commonly abused by this population, thus, there is a great and
increasing need to study HAND and understand HIV-associated neuropathogenesis to develop better treatment
options and improve disease management. However, these efforts are significantly hampered by the lack of a
physiologically relevant brain/CNS model. To address this need, we developed a cutting-edge tri-culture human
3D-brain organoids (hBORGs) that contains primary neurons, astrocytes and microglia (HIV-1-infected and
uninfected) to accurately model the brain environment, chronic virus replication, and neuroinflammatory milieu
observed in HIV-1 infected individuals. Using this 3D-BORG model, we propose to test our hypothesis that
neuroinflammation caused by HIV-1 infected microglia, induces degeneration of neurons, synaptic pruning and
loss of dendrites, astrocytosis and these effects worsen by the addition of oipoid drug abuse. We propose the
following aims to achieve the goals: Aim 1. Delineate how infected microglia contribute to pruning and scaling of
synaptodendrites, loss of synaptic functions and neuronal loss; Aim 2. Determine how use of illicit drugs such as
Morphine drives the development and/or worsening of the neuronal dysfunction and pathology; and Aim 3.
Identify the how viral and cellular factors from HIV-1 infected microglia cause the HAND-associated pathological
features. We have assembled a team of investigators who have expertise in HIV-1 Virology, 3D-Organoids and
drug abuse and synaptic function, thus, are poised to define how infected microglia interact with neurons and
astrocytes and further delineate the molecular mechanisms involved in dendritic damage, synaptic plasticity and
neuronal survival in the presence and absence of drug abuse. This will help us develop novel therapeutics that
can prevent neuronal damage and loss of synaptic function and cognitive impairment observed in PLWH.

## Key facts

- **NIH application ID:** 10651458
- **Project number:** 1R56NS122567-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** VELPANDI AYYAVOO
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $686,284
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10651458

## Citation

> US National Institutes of Health, RePORTER application 10651458, Modeling HIV-1 Neuropathogenesis and neuronal dysregulation using 3D-organoids containing multiple CNS cell lineages (1R56NS122567-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10651458. Licensed CC0.

---

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