# The role of ATRX in both promoting the establishment of HSV latency and restricting reactivation

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $537,857

## Abstract

The human pathogen, Herpes Simplex Virus (HSV), establishes latency only in neurons and can reactivate to
result in the production of infectious virus for transmission to a new host. Reactivation can result in lesions at
the body surface and encephalitis, in addition to potentially promoting the development of neurodegenerative
disease. Our previous work has found that the latent HSV genome is associated with repressive heterochro-
matin. Therefore, entry and maintenance of HSV latency are likely regulated by the nuclear environment in the
neurons, although specific proteins that function in neurons to promote heterochromatin-based silencing of the
viral genome are not known. We have found that the heterochromatin-associated protein, Alpha-Thalasse-
mia/mental Retardation X-linked (ATRX), is highly abundant in neurons. ATRX is a multi-functional, hetero-
chromatin-associated protein, and mutations in ATRX are associated with neurodevelopment disease. The role
of ATRX in neuronal development suggests a specific role for ATRX in modulating gene expression in neu-
rons. Importantly, we have found that ATRX is required to limit HSV gene expression in neurons and promote
entry into latency. Once latency is established, we have found that HSV genomes are associated with ATRX,
and these genomes are also enriched for histone H3 tri-methyl lysine 9 (H3K9me3). Furthermore, we have
found that ATRX acts as a barrier to HSV reactivation in response to cell stress. The goals of this project are to
determine the mechanistic functions of ATRX in regulating different stages of HSV latency. Based on our pre-
liminary data, we hypothesize that ATRX promotes the formation of H3K9 methylation to limit gene expression
and promote entry into latency (tested in aim 1). We also hypothesize that once latency is established, ATRX
binds to a sub-population of viral genomes that are enriched for the H3K9me3 modification and prevents lytic
gene expression occurring from these genomes (tested in aim 2). We will use our expertise in animal models
of HSV latency, in addition to in vitro models of HSV latency and reactivation established in our lab, to test
these hypotheses. In aim 1, we will determine the contribution of ATRX in deposition and spreading of the
H3K9me3 modification, in addition to the role of H3K9me3 in promoting entry into latency. In aim 2, we will de-
termine the mechanistic function of ATRX in preventing transcription from H3K9me3-associated genomes in
response to multiple reactivation stimuli. Therefore, this proposal is significant and innovative because it will
mechanistically determine the contribution of an abundant neuronal protein to both promoting HSV latency and
preventing reactivation. Understanding this is crucial because it may be possible to utilize the role of ATRX to
develop therapies that prevent HSV reactivation. Given that mutations to the H3K9me3 reading domain of
ATRX are associated with neurodevelopmental diseases, understanding the mecha...

## Key facts

- **NIH application ID:** 10986620
- **Project number:** 1R01NS135166-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Anna Ruth Cliffe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $537,857
- **Award type:** 1
- **Project period:** 2024-05-15 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10986620

## Citation

> US National Institutes of Health, RePORTER application 10986620, The role of ATRX in both promoting the establishment of HSV latency and restricting reactivation (1R01NS135166-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10986620. Licensed CC0.

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