# Regulation of HIV latency by microglial-neuronal interactions

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $790,503

## Abstract

Summary
 Over 40% of HIV-positive individuals in the United States engage in substance use. This
not only represents a major cause of enhanced morbidity and mortality, but also is associated
with increased risks of neurocognitive disorders, such as HAND. Neurons possess refined
systems for maintaining constant communication with glia through propagation of “Off” and “On”
signals controlling microglial activation states. Using HIV latency models in immortalized human
microglial cells (hµglia/HIV), we have shown previously that cellular activation and inflammatory
responses induce HIV production. Remarkably, co-culture of productively infected microglia with
an excess of healthy neurons leads to viral silencing. We have also shown that hµglia/HIV cells
can migrate into brain organoids where they become silenced. However, damaging neurons with
a variety of agents, including methamphetamine (METH), a frequently-used abuse substance
among HIV-infected individuals, produce reactivation signals for HIV, and this initiates a cycle of
microglial activation and further neuronal damage. This cycle of shutdown and reactivation seems
to parallel the M1 to M2 transition model of microglial cells, much as HIV latency in T cells is a
product of the natural transition of effector cells to resting memory cells. In this proposal, we seek
to define the key signals mediating the cycle of viral silencing and reactivation in microglial cells
by neurons in the context of iPSC-derived cerebral organoids. This multidisciplinary investigation
is designed as a close collaboration between the laboratories of Dr. Jonathan Karn (CWRU, HIV
molecular biology), Dr. Anthony Wynshaw-Boris (CWRU, iPSC cells, brain organoids), Dr. Kurt
Hauser (VCU, neurobiology and drug abuse), and Dr. Pamela Knapp (VCU, brain organoids). To
avoid the limitations of working with transformed cells, we have recently initiated experiments
using co-cultures between iPSC-derived cerebral organoids and microglia. Using co-cultures
between iPSC-derived cerebral organoids and microglia, we will thoroughly test the hypothesis
that the exaggerated responses of HIV-infected microglia to neuronal damage leads to enhanced
neurodegeneration. We will also test the hypothesis that exposure to METH, given this
background of faulty microglia-neuron crosstalk, enhances HIV replication. Using genome editing
approaches, we will identify the specific contribution of “On” and “Off” receptor systems in
controlling HIV latency in microglia, and study how METH impacts neuronal-microglial signaling
to augment HIV production. In parallel with our genetic investigations, we will also evaluate a
number of pharmacological agents against microglial receptors, HIV transcription inhibitors, and
mediators of inflammation in order to define therapeutic approaches that might be expected to
slow the development of HAND, especially in patients who abuse drugs.

## Key facts

- **NIH application ID:** 10220927
- **Project number:** 5R01DA049481-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** JONATHAN KARN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $790,503
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220927

## Citation

> US National Institutes of Health, RePORTER application 10220927, Regulation of HIV latency by microglial-neuronal interactions (5R01DA049481-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220927. Licensed CC0.

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