# Understanding the mechanisms involved in HIV-1 CNS latency

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $793,032

## Abstract

In people with HIV (PWH), infected cells persist in several tissue compartments, including
brain and lymphoid organs, and can remain indefinitely during combination antiretroviral therapy
(cART). This persistence is due to the ability of the virus to establish a state of latency in cells,
where the proviral DNA remains transcriptionally silent for long periods. The central nervous
system (CNS) is considered one of the viral reservoirs due to the blood-brain barrier, resulting in
cellular compartmentalization and limited penetrability of some antiretroviral drugs. The primary
cells that serve as reservoirs in the CNS compartment are microglia, macrophages, and
astrocytes; however, very little is known about HIV-1 infection of these cells and the establishment
of HIV-1 reservoirs in the CNS. Studies evaluating latent resting CD4+ T cells in the periphery
have shown that epigenetic regulation, histone modification, transcriptional control and
methylation in the 5' HIV-1 long terminal repeat (LTR), which serves as the viral promoter,
facilitates viral latency. However, there remains limited understanding of how viral latency is
promoted and maintained in CNS microglia and macrophages. Accordingly, this proposal aims to
identify the key factors, pathways and their regulators, which determine the establishment and
reactivation of latent virus in the CNS. We hypothesize that HIV-1 latency establishment,
maintenance and reactivation in brain myeloid cell lineages are controlled by unique cellular
factors and their regulators specific to the CNS milieu that are distinct from latently infected CD4+
T cells in the periphery. Using our recently developed in vitro multicell lineage 3D-CNS organoids
with microglia from brains of HIV-1 positive donors, and infiltrating monocytes, a humanized
mouse model with infected microglia, and a precise Systems Biology approach, we will define the
on-off switches involved in myeloid cell reservoirs at the single cell level and HIV-1 latency in the
CNS. Successful completion of this study will identify new therapeutic targets (activators and
silencers) that are unique for myeloid cells in the CNS. A better understanding these factors can
improve treatment of PWH and can contribute to the development of a HIV-1 cure.

## Key facts

- **NIH application ID:** 10933086
- **Project number:** 1R01MH136952-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** VELPANDI AYYAVOO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $793,032
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933086

## Citation

> US National Institutes of Health, RePORTER application 10933086, Understanding the mechanisms involved in HIV-1 CNS latency (1R01MH136952-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10933086. Licensed CC0.

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