# Mechanisms controlling HIV latency and pathogenesis in microglia

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $434,500

## Abstract

PROJECT SUMMARY
The life expectancy of people with HIV (PWH) has improved significantly in the past decades with the introduction
of antiretroviral therapies (ART). Nevertheless, the risk for developing comorbidities including HIV-associated
neurocognitive impairment even in “well-controlled” PWH is significantly increased. One obstacle to the
eradication of HIV and treatment of HIV-associated neurocognitive impairment is the lack of knowledge about
the epigenetic mechanisms of HIV in microglia. Specifically, little is known about the extent of HIV integration
into the host’s genome, specifically that of microglia, in PWH under ART; the viral and epigenetic gene regulatory
mechanisms regulating HIV latency and neuropathogenesis; and whether the integrated HIV provirus is intact or
defective, potentially inducing a chronic immune response in the brain.
 To address these knowledge gaps, we will use archived human post-mortem specimens obtained from
the National NeuroAIDS Tissue Consortium (NNTC) as well as microglia-like cells generated from human
induced pluripotent stem cells (iPSC-MG). We will use single cell multi-omics (RNA/ATAC-Seq) approaches to
specifically obtain the transcriptomic and epigenomic landscapes of the viral and host genomes using single cell
technologies. To decipher the epigenetic landscape including the potentially altered histone modification
landscape of microglia and HIV, we will perform in addition ChIP-seq. Our proposed investigations are strongly
supported by compelling preliminary data providing a gene expression and chromatin accessibility atlas of
human microglia isolated from three PWH. In addition, we propose a novel approach to identify viral integration
sites in microglia from human post-mortem samples and iPSC-MG using state-of-the-art Long-read sequencing
and artificial intelligence technologies technology. We will use our established iPSC-MG HIV model system to
further test the effect of ART on the epigenetic landscape, including histone modification and transcription factor
binding, to understand the mechanisms regulating HIV latency and neuropathogenesis.
 In Aim 1, we will identify microglia gene expression signatures and their underlying gene regulatory
mechanisms in HIV infection. For Aim 2, we will establish Long-read sequencing to decipher HIV-integration
sites. In Aim 3, we will use iPSC-MG to identify the viral epigenetic landscape in microglia in the presence and
absence of ART.

## Key facts

- **NIH application ID:** 10748702
- **Project number:** 1R21MH134401-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Johannes Carolus Magnus Schlachetzki
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $434,500
- **Award type:** 1
- **Project period:** 2023-08-14 → 2025-08-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10748702

## Citation

> US National Institutes of Health, RePORTER application 10748702, Mechanisms controlling HIV latency and pathogenesis in microglia (1R21MH134401-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10748702. Licensed CC0.

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