# Stress-Mediated Regulation of HSV-1 Reactivation from Latency

> **NIH NIH R01** · OKLAHOMA STATE UNIVERSITY STILLWATER · 2024 · $341,013

## Abstract

Project Summary & Abstract
Herpes simplex virus 1 (HSV-1), an important human pathogen, establishes life-long
latency in neurons within trigeminal ganglia (TG) and CNS, including brainstem.
External stressors periodically trigger reactivation from latency, resulting in recurrent
ocular disease and encephalitis. The synthetic corticosteroid dexamethasone
significantly enhances reactivation from latency in HSV-1 latently infected mice.
Conversely, a glucocorticoid receptor (GR) antagonist significantly reduces reactivation
from latency. A transcription factor activated by the Wnt pathway, b-catenin, is
expressed in more TG neurons during latency relative to stress induced reactivation
suggesting b-catenin maintains latency. GR and a stress induced transcription factor,
Krüppel like transcription factor 15 (KLF15), form a feed forward loop that synergistically
transactivates viral immediate early promoters required for productive infection. Based
on these exciting unpublished studies, we hypothesize that stress, via GR activation, has
multi-pronged effects on the latency-reactivation cycle. An important early step during
reactivation is a stressful stimulus disrupts latency by suppressing the canonical Wnt/b-
catenin signaling pathway. A second early step is GR and KLF15 cooperatively
stimulate viral gene expression, ultimately leading to virus production. Studies in this
proposal will directly test this hypothesis. For Aim 1, HSV-1 reactivation from latency will
be compared in mice that do not express GR in TG or KLF15 knockout mice relative to
wild-type mice. For Aim 2, we will investigate how GR and KLF15 synergistically
activate viral transcription. Finally, differentially expressed genes associated with the
Wnt/b-catenin signaling pathway will be identified during latency and reactivation from
latency (Aim 3). Completion of these studies will reveal how stress disrupts latency and
directly stimulates viral gene expression.
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## Key facts

- **NIH application ID:** 10782471
- **Project number:** 5R01NS111167-05
- **Recipient organization:** OKLAHOMA STATE UNIVERSITY STILLWATER
- **Principal Investigator:** CLINTON J JONES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $341,013
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782471

## Citation

> US National Institutes of Health, RePORTER application 10782471, Stress-Mediated Regulation of HSV-1 Reactivation from Latency (5R01NS111167-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10782471. Licensed CC0.

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