# Epigenetic profiling of HIV-associated neuroinflammation and proviral expression in the brain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $818,886

## Abstract

Abstract
Background: HIV infection in the brain occurs early after transmission and leads to chronic neuroinflammation.
Although modern antiretroviral therapy (ART) controls viral replication, there is no cure for HIV, and successful
control of viral replication has not completely ameliorated inflammation and HIV-associated
neurocognitive disorders (HAND). Microglia play a central role in other neurodegenerative disorders and are
the likely primary reservoir for HIV in the brain, but little else is known about the inflammatory character
associated with HAND. Additionally, the inflammatory incitement associated with HIV is potentially determined
by its expression of viral proteins, dictated by the epigenetic microenvironment of the provirus, which is poorly
characterized. Recently, the Nurr1 receptor was described as an important mediator of HIV-1 silencing in the
context of microglia in vitro, making it a prospective focal point for further studies in brain tissue.
Study Cohort: We will leverage the unique Last Gift rapid autopsy cohort, which allows us to preserve cellular
integrity and nucleic acids in precious tissue samples collected from PWH. We will select frontal cortex and basal
ganglia from 15 Last Gift participants to analyze for this proposal.
Our goal: Using powerful single cell sequencing techniques, we will characterize the epigenetic regulators of the
HIV provirus in brain myeloid cells from 15 PWH using novel epigenetic enrichment techniques and assimilated
data on integration sites and the full-length proviral sequence generated as part of the Last Gift project (Aim 1).
Next, using brain myeloid cells isolated from a subset of the participants (N=6), we will further explore the
mechanistic framework of the HIV provirus in microglia through manipulation of the proviral epigenetic profile
using in vitro Nurr1 agonists and epigenetic modulators (Aim 2). Finally, we will use single cell techniques to
examine the epigenetic and transcriptomic profile of the inflammatory milieu in the brains of PWH on suppressive
ART and correlate them with proviral load and cell-associated viral RNA (Aim 3).
How will we advance the field? The epigenetic characteristics of the HIV provirus have not been examined in the
brains of people with HIV (PWH). Most evaluation of proviral epigenetics has been focused upon CD4+ T cells,
but thus far few have examined epigenetic mechanisms of proviral reactivation in microglia from PWH, and none
have been able to define these mechanisms thoroughly in tissue samples or cells isolated from brains of PWH.
Therefore, this proposal will advance our understanding of HIV persistence in the brain on multiple fronts.
Additionally, the inflammatory pathogenesis of NCI in HIV infection is poorly characterized, but our proposal
would not only allow definition of the immune cell character in the brains of PWH, but also the epigenetic and
transcriptomic mechanisms at play in all cell types, including neurons and astrocytes.

## Key facts

- **NIH application ID:** 10924866
- **Project number:** 1R01NS137852-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Sarah Adrianne LaMere
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $818,886
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10924866

## Citation

> US National Institutes of Health, RePORTER application 10924866, Epigenetic profiling of HIV-associated neuroinflammation and proviral expression in the brain (1R01NS137852-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10924866. Licensed CC0.

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