# Regulation of HSV latency by Polycomb Silencing

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $713,629

## Abstract

Project Summary/Abstract
Reactivation of viruses from latent infection can result in series disease. In addition, latent infections are a
barrier to curing certain viral diseases. For the persistent herpesvirus, Herpes Simplex Virus (HSV), the
mechanisms that regulate entry of the virus into a latent infection are not known. The formation of
heterochromatin on the viral genome in neurons has long been hypothesized to contribute to suppressing gene
expression for latency establishment. However, no functional studies have yet identified a role for
heterochromatin formation as a mechanism to promote entry into latency or maintain a latent infection. There
are multiple different types of heterochromatin, which differ their mechanisms of gene silencing and ability to
be reversed for gene expression to take place. Our overall hypothesis is that HSV actively promotes a type of
heterochromatin to enable both persistence and reactivation. Our data indicate that the histone modification,
H2AK119ub1, is enriched on the HSV genome during latency. H2AK119ub1 functions to repress gene
expression, but it is also known to be rapidly remodeled to permit gene expression to take place in response to
certain stimuli. Importantly, our preliminary data indicate that H2AK119ub1 needs to be deposited onto HSV
genomes to later enable reactivation to occur. To understand the contribution of H2AK119ub1 to HSV latency
and reactivation, along with the mechanism of H2AK119ub1 deposition on the genome, complementary in vitro
and in vivo models of HSV latency are essential. Our lab has developed novel in vitro model systems to
investigate the molecular mechanisms of HSV latency establishment and reactivation, which we combine with
high-resolution imaging to investigate the association of individual viral genomes with chromatin-associated
proteins. These assays will be complemented with epigenetic assays to map and quantify protein association
with viral genomes in vitro and in vivo. In aim 1, we will investigate how H2AK119ub1 impacts the
establishment of latency. In aim 2, we will determine how the protein complex responsible for H2AK119ub1 is
recruited to viral genomes via interacting with the HSV long non-coding RNA known as the Latency Associated
Transcript. In aim 3, we will examine why H2AK119ub1 association is required for the formation of reactivation
competent latent infection. Upon completion of these aims, we will understand how heterochromatin is targeted
to the HSV genome to limit lytic gene expression specifically in neurons and therefore promote latency
establishment. We will answer a long-standing question on the mechanistic function of the Latency Associated
Transcript in regulating latency establishment and reactivation. Finally, we will understand how different types
of heterochromatin modulate the ability of HSV to undergo reactivation. Ultimately, we will identify targets for
therapeutics that could act to directly prevent latency establishment or reactivat...

## Key facts

- **NIH application ID:** 10888468
- **Project number:** 1R01AI177341-01A1
- **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:** $713,629
- **Award type:** 1
- **Project period:** 2024-06-07 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888468

## Citation

> US National Institutes of Health, RePORTER application 10888468, Regulation of HSV latency by Polycomb Silencing (1R01AI177341-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10888468. Licensed CC0.

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