# Epigenetic HIV Silencing in Macrophages

> **NIH NIH R33** · UNIVERSITY OF PENNSYLVANIA · 2020 · $862,319

## Abstract

Project Summary/Abstract - Epigenetic HIV Silencing in Macrophages
Antiretroviral therapy (ART) is highly effective in HIV infection but has substantial limitations, and strategies to
achieve an aviremic state without ART (“functional cure”) are a focus of great interest. A potential approach to
prevent persistent viral reservoirs from giving rise to replicating virus once ART is stopped is to silence HIV in
these reservoirs so infection cannot “re-ignite”. Infected macrophage lineage cells serve as the main long-term
reservoir for HIV in the CNS, which is believed to be a “sanctuary site” where virus can persist even if extra-
CNS reservoirs are purged. Furthermore, long-lived infected macrophages may continue to produce low levels
of virus, which contributes to HIV-associated neurocognitive disorders (HAND). Thus, silencing HIV in
macrophages may both contribute to “functional cure”, and ameliorate HAND in the setting of ART suppression.
HIV integrates into the host cell genome and is subject to positive and negative epigenetic regulation. Much
work has been done on epigenetic control of HIV in T cells, but less is known in macrophages. Chromatin
organization and transcriptional regulation is highly cell and context-specific. Our scientific premise is that
macrophages in the CNS fail to epigenetically suppress HIV and serve as a long-term reservoir. We
hypothesize that macrophage-specific enhancer-promoter interactions regulate persistent HIV transcription
activity, and that small molecules can reprogram epigenetic regulation of HIV infected macrophages to
establish long-term silencing of the integrated HIV genome. To this end, we have established a primary
macrophage model for high-throughput screening of small molecule modulators of epigenetic enzymes, and
provide preliminary evidence for involvement of dioxygenase enzymes involved in histone demethylation.
In Phase 1, we will optimize primary & secondary assays for a high-throughput screening campaign to identify
small molecule epigenetic regulators of HIV-1 expression in primary human macrophages; test the role of
candidate epigenetic modulators, especially histone & DNA demethylases that may prevent HIV silencing; and
further investigate molecular mechanisms that regulate persistent HIV transcription in macrophages. In Phase
2, we will perform a high-throughput screen to develop small molecules to silence HIV-1 in macrophages using
industry-standard milestone-driven drug discovery pipeline to identify bioactive chemotypes; validate lead
compounds with primary HIV isolates & myeloid cell types; advance drug-like properties of candidate hits
through medicinal chemistry; and define molecular targets and conduct mechanism of action studies.
At the end of Phase I we will have a robust high-throughput primary cell-based screen, orthogonal validation
assays to confirm on-target hits, and further insight into macrophage-specific epigenetic factors regulating HIV.
At the end of Phase 2, we will com...

## Key facts

- **NIH application ID:** 10205406
- **Project number:** 4R33AI133696-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ronald G Collman
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $862,319
- **Award type:** 4N
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205406

## Citation

> US National Institutes of Health, RePORTER application 10205406, Epigenetic HIV Silencing in Macrophages (4R33AI133696-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10205406. Licensed CC0.

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