# Toward Understanding the Role of Adult Human Microglia in the Ongoing Persistence of HIV and its Associated Neuropsychiatric Comorbidities

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2021 · $204,688

## Abstract

PROJECT SUMMARY
Despite effective suppression of HIV replication, current treatments do not provide sterilizing immunity or
eradicate anatomical reservoirs. Studies conducted in HIV animal models and infected humans demonstrate the
strong likelihood that the brain's long-lived microglia (MG) play an essential role in reservoir
formation/maintenance. Elevated inflammatory cytokines and infected immune cells with HIV DNA have been
found in the CSF of HIV-infected people on antiretroviral therapy (ART), revealing the increased risks to brain
health and homeostasis. However, a deep understanding of the molecular mechanisms at work in human MG-
HIV host-pathogen interaction that foments reservoir formation and maintenance has been very difficult and until
recently, near intractable to study. Three key limitations must be overcome to achieve progress. First, is the
limited ability to procure large quantities of adult human MG for experimentation. Second, cultured human MG
must be relatively long-lived in vitro in order to conduct antiretroviral treatment interruption and reactivation
studies. Third, to advance translational goals, an in vivo model to test the full complement of human adult MG
function is needed and to validate mechanistic findings obtained in vitro. Exciting progress by several groups
has been made on these fronts. Mathews et al., reported on the successful engraftment and HIV infection of
human MG derived from fetal cord blood progenitors into the brains of NOG-IL-34 transgenic mice. A recent
study by Rai et al., comparing transcriptomes found ~78% conservation in a previously validated MG conserved
gene signature between human blood monocyte-derived MG, iPSC-derived human MG and human tissue adult
MG that was not shared with two MG cell lines suggesting a possible path forward. Collectively, these data show
that a subset of blood myeloid progenitors found in both mouse and man, retain genetic plasticity and resiliency
built into a biological system that is overall crucial for proper brain functioning. The goals of this exploratory
proposal are to build upon advances in culturing adult human MG from blood myeloid progenitors to allow study
of somatic genetics and improve the translational potential of neuroHIV in vitro and in vivo experimental models.
The long-term goal is to decipher the contribution of microglia and inflammatory stimuli to the maintenance of
the HIV CNS reservoir. The Specific Aims are to: 1) characterize the extent, breadth and fidelity of human blood
myeloid progenitors from unrelated adult healthy donors to populate and serve as HIV reservoirs in the brain and
2) identify and study the hierarchy of proinflammatory gene network expression kinetics in HIV-infected adult
human microglia and impact on HIV persistence during ART. The findings from the proposed studies will lay the
groundwork for deeper investigation of MG function, proinflammatory signaling, and the potential development
of novel strategies for identi...

## Key facts

- **NIH application ID:** 10330823
- **Project number:** 1R21MH128152-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** AMANDA MARIA BROWN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $204,688
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330823

## Citation

> US National Institutes of Health, RePORTER application 10330823, Toward Understanding the Role of Adult Human Microglia in the Ongoing Persistence of HIV and its Associated Neuropsychiatric Comorbidities (1R21MH128152-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10330823. Licensed CC0.

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