# Neuron Specific Regulation of HSV1 and HSV2 Outcomes of Infection

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $339,914

## Abstract

Neuron Specific Regulation of HSV1 and HSV2 Outcomes of Infection
Abstract
Our overall goal is to identify how different types of neurons regulate viral infections to produce divergent
outcomes of lytic, latent or reactivating infections. It is well-established that herpes simplex viruses (HSV1 and
HSV2) establish latency in sensory and autonomic neurons, from which they can reactivate to cause recurrent
disease. However, some types of neurons support HSV replication upon entry, while other types naturally
inhibit viral replication, resulting in latency. Exogenous stimuli can trigger reactivation, but only from a portion of
these latently infected neurons. The neuronal populations that support these divergent outcomes differ for
HSV1 and HSV2, leading to different anatomical patterns and frequencies of recurrent disease. To fully
understand how mature sensory neurons permit or inhibit viral replication, it is essential to study these
mechanisms in the appropriate neurons. We have determined that in adult sensory neurons, continuous
presence of glial cell derived neurotrophic factor (GDNF) and neurturin (NTN) maintain HSV latency through
their receptors, GFR1 and GFR2. Deprivation of GDNF or NTN selectively induces HSV2 or HSV1
reactivation. GFR1/2 signaling through RET activates several downstream signaling pathways to maintain
cellular function, and also maintains the presence of proteins bound to specific regions of the viral genome.
The central hypothesis of this proposal is that that GDNF and NTN continuously signal through RET to
maintain HSV1 and HSV2 in a latent state in adult sensory neurons. Furthermore, continuous signaling
deposits inhibitory neuronal proteins onto the viral genome, including chromatin modifications
associated with inactive gene transcription. Using our innovative primary adult sensory neuronal cultures,
combined with an in vivo model that recapitulates the different HSV1 and HSV2 recurrence patterns, we will 1)
identify the neuronal signaling pathways through which neurotrophic factors regulate HSV1 and HSV2
infections, 2) determine how neurotrophic factors maintain the latent state of the viral genome, and 3)
determine how neurotrophic factor deprivation differentially induces HSV1 and HSV2 reactivation in vivo. The
rationale that drives this project is that by identifying neuronal factors and mechanisms that naturally prevent
HSV replication and reactivation in specific types of neurons, we can identify targetable neuronal pathways and
factors to permanently lock the virus into a latent state incapable of reactivation, in any type of neuron.

## Key facts

- **NIH application ID:** 10146496
- **Project number:** 5R01NS104351-04
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Andrea S Bertke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,914
- **Award type:** 5
- **Project period:** 2018-06-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146496

## Citation

> US National Institutes of Health, RePORTER application 10146496, Neuron Specific Regulation of HSV1 and HSV2 Outcomes of Infection (5R01NS104351-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10146496. Licensed CC0.

---

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