# HSV latency and reactivation in a human sensory neuronal model system

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2024 · $236,911

## Abstract

The human pathogen, Herpes Simplex Virus-1 (HSV-1), establishes latency in neurons and can reactivate,
resulting 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, HSV-1 infection in North American is shifting to become more
associated with genital infection, which results in painful lesions, sexual transmission and an enhanced risk of
transmission to neonates. There are currently no therapies that target the latent or reactivation stage of HSV-1
infection. In addition, there is increased viral resistance to current therapeutics along with toxicity associated
with their use. Therefore, new therapies are required that can prevent HSV reactivation. However, to develop
new therapies we need a better understanding of the molecular basis of HSV latency and reactivation.
Because HSV establishes latency in neurons, developing model systems has been a challenge. Current
models largely rely on murine primary neurons, which, while informative, have limitations; they are not easily
scalable and are not of the same host species. Our lab has considerable expertise in creating and
characterizing in vitro models of HSV latency, including the development of a recombinant Stayput-GFP virus
model that allows latency to be established in murine in vitro neurons without requiring anti-viral drugs. We
have also characterized the nature of the chromatin on viral genomes during latency and investigated a
biphasic wave of viral gene expression that is unique to reactivation. Therefore, the goals of this project are to
use our expertise to develop and characterize a model of HSV-1 latency in human sensory neurons
differentiated from a cell line derived from the dorsal root ganglion. Notably, genital HSV-1 infection results in
latency in dorsal root ganglia neurons. The aims are based on our preliminary data indicating that we can
establish latency in this system using Stayput-GFP and induce reactivation using a combination of triggers. In
the first aim, we will comprehensively characterize the system, focusing on viral gene expression, the
epigenetic composition of the viral genome, and the role of a known cell stress pathway in inducing a
reactivation-specific biphasic wave of viral gene expression. In the second aim, we will fully determine the type
of sensory neurons produced and use the system to investigate the epigenetic structures of HSV genomes and
differing abilities to reactivate from different neuronal subtypes. In conclusion, this proposal will result in the
creation of an easily scalable model in human sensory neurons that does not require antiviral drugs to promote
latency establishment. We will also, for the first time, define the epigenetic structure of the viral genome in
human neurons. Finally, we will use clinically relevant inhibitors to determine the contribution of a neuronal cell
stress pathway in exit of HSV from latency in human neurons. There...

## Key facts

- **NIH application ID:** 10973764
- **Project number:** 1R21AI185862-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Anna Ruth Cliffe
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $236,911
- **Award type:** 1
- **Project period:** 2024-06-03 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973764

## Citation

> US National Institutes of Health, RePORTER application 10973764, HSV latency and reactivation in a human sensory neuronal model system (1R21AI185862-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10973764. Licensed CC0.

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