# The hCNS-HIV/ARV assay system, a platform utilizing human iPSC-neurons/-microglia/-astrocytes to test HIV/AIDS therapeutics for neurotoxicity related to HIV-associated cognitive disroder (HAND)

> **NIH NIH R44** · VALA SCIENCES, INC. · 2022 · $940,992

## Abstract

Globally, about 40 million people live with HIV/AIDS, and HIV antiretroviral agents (ARVs) are a multi-billion
dollar pharmaceutical sector with continued development of agents. Thanks to combination antiretroviral
therapy (cART, in which 2 to 4 ARVs are given, simultaneously) HIV+ people have a near-normal life-span.
HIV+ pregnant women also receive cART, and their children are given cART prophylactically at birth (in
general, cART is given to all HIV+ infants and children). For all HIV+ patients, if cART is stopped, HIV
replication restarts; thus, HIV+ people must remain on cART for the rest of their lives. For HIV+ adults, ARVs
are present during aging, in which loss of central nervous system (CNS) neurons contributes to loss of
cognition/dementia. For HIV+ infants and children, ARVs are present during neurodevelopment. HIV+
individuals frequently develop HIV-Associated Cognitive Disorders (HAND), which includes HIV-associated
dementia (HAD,common in AIDS), and less severe forms (asymptomatic neurocognitive impairment and mild
neurocognitive disorder (MND). While cART has reduced the incidence of HAD, ANI and MND remain at high
levels, even when HIV load is very low. In fact, certain ARVs may contribute to HAND, and alarmingly,
HIV+children on cART exhibit developmental delays in intellectual performance. Also, HIV infects/replicates in
microglia (MG), an innate immune cell of the CNS, and MG are out of the reach of ARVs that are poor at
crossing the blood:brain barrier. More brain-penetrant ARVs were developed, but, unexpectedly, these are
linked to greater incidence of HAND. Preclinical research on ARV neurotoxicity has been conducted on primary
rodent neurons and glial. Our goal is to develop an assay system (dubbed the hCNS-HIV/ARV platform) for
testing ARVs for neurotoxicity and efficacy at inhibiting HIV, neurons, MG and astrocytes (another glial cells),
derived from human induced pluripotent stem cells (hiPSC-neurons, hiPSC-MG, and hiPSC-ACs). In phase I,
we developed methods for testing ARVs on hiPSC-neurons plated in 384-well dishes, utilizing high-throughput
digital microscopy/analysis. We found neurotoxicity (reductions in neurites, synapses, and calcium transients)
for elvitegravir (EVG, strongest effect, matching data with rat neurons), dolutegravir (DTG, linked to birth
defects), and tenofovir disoproxil fumerate (TDF) and certain combinations of ARVs representing cART had
stronger effects than the ARVs, alone. TDF also reduced the viability and elicited epigenetic changes in human
neural precursor cells (hNPCs), suggesting that TDF may affect neurogenesis, a process critical for
neurodevelopment and cognition. In phase II we will develop standard assay protocols/analysis methods for
testing ARVs and HIV infection, itself, on hiPSC-neurons/-MG/-ACs, and on hiPSC-NPCs. The hCNS-
HIV/ARV platform will enable development of ARVs that inhibit HIV with minimal neurotoxicity and will be
marketed to pharmaceutical companies developing n...

## Key facts

- **NIH application ID:** 10397158
- **Project number:** 5R44MH119621-03
- **Recipient organization:** VALA SCIENCES, INC.
- **Principal Investigator:** PATRICK M MCDONOUGH
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $940,992
- **Award type:** 5
- **Project period:** 2018-09-10 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397158

## Citation

> US National Institutes of Health, RePORTER application 10397158, The hCNS-HIV/ARV assay system, a platform utilizing human iPSC-neurons/-microglia/-astrocytes to test HIV/AIDS therapeutics for neurotoxicity related to HIV-associated cognitive disroder (HAND) (5R44MH119621-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10397158. Licensed CC0.

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