# IFN-dependent repression of HSV latency by PML-nuclear bodies

> **NIH NIH R21** · UNIVERSITY OF VIRGINIA · 2020 · $201,875

## Abstract

Project summary/abstract
Herpes simplex virus (HSV) establishes a life-long latent infection in neurons. Periodically, HSV reactivates
from latency, which can lead to productive replication at the body surface, often resulting in clinical symptoms.
Diseases resulting from HSV reactivation includes cold sores, genital lesions and ocular disease, which can
manifest as keratitis or endotheliitis. Transmission to the central nervous system following reactivation can
result in herpes simplex encephalitis (HSE). Without treatment, HSE has a fatality rate of 70%, and even with
treatment, many survivors exhibit long-term sequelae. There is evidence that HSV latency is heterogenous in
terms of the association of viral genomes with different subnuclear structures, which may result in different
abilities of latent genomes to reactivate. In some neurons, HSV genomes associate with subnuclear, phase-
separated structures known as PML-NBs. We were interested to determine the contribution of PML-NBs to
HSV latency and reactivation. Surprisingly, we found that PML-NBs are not present in either sensory or
sympathetic primary murine neurons but do form upon treatment with interferon (IFN), in particular type I IFN.
HSV can establish latency in the absence of IFN. However, IFN treatment at the time of infection results in a
more restricted form of latency that is less capable of undergoing reactivation, which is reversed following PML
depletion. These data imply that IFN exposure during the initial window of HSV infection can have a long-term
effect on the reactivation potential of the virus in a PML-dependent manner. We will test this using in vitro and
in vivo models of latency in which PML is conditionally knocked-out in neurons. Viral genomes associated with
PML-NBs have been found to express lower levels of the HSV latency-associated transcript (LAT). Therefore,
we will also examine the effects of PML knock-out on LAT expression and investigate the direct versus indirect
effects of PML using LAT deletion viruses. To determine why viral genomes associated with PML-NBs are
more restricted for reactivation we will investigate the role of PML-NBs in the association of viral genomes with
core histones and different repressive histone post-translational modifications and heterochromatin-associated
proteins. We will also perform dSTORM super-resolution microscopy on latent viral genomes to determine the
physical structure of viral genomes found in proximity to phase-separated PML-NBs. Our long-term goals are
to understand how different forms of HSV latency arise and ultimately how to modify the latent genome into its
most repressive form so that it is refractory to reactivation.

## Key facts

- **NIH application ID:** 9953898
- **Project number:** 1R21AI151340-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Anna Ruth Cliffe
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $201,875
- **Award type:** 1
- **Project period:** 2020-02-20 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953898

## Citation

> US National Institutes of Health, RePORTER application 9953898, IFN-dependent repression of HSV latency by PML-nuclear bodies (1R21AI151340-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9953898. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*