# Ocular HSV: Mechanism of virus reactivation

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $417,500

## Abstract

Project Summary
 Reactivation of HSV in latently infected sensory neurons is of considerable clinical importance
especially with respect to eye disease. Development of effective alternative strategies to limit reactivation has
been limited by an insufficient understanding of mechanisms that regulate intermittent reversion from the latent
to the infectious state. HSV latency associated transcript (LAT) plays a critical role in latency-reactivation and
is the only viral transcript detected at high levels in infected sensory neurons of humans, mice, and rabbits.
Because the viral genome, but no detectable infectious virus, is present in latent HSV infection, it is clear that
the viral genome is not fully quiescent in latently infected cells. Our previous studies, and those published in
the current funding period, established an important link between gD expression and the ability of LAT to
enhance herpes virus entry mediator (HVEM) expression in TG of latently infected mice. Our findings suggest
a novel model, in which gD expression and LAT enhanced upregulation of HVEM expression contribute to HSV
reactivation in TG of latently infected mice. In this proposal, we hypothesize that low level gD expression
and its binding to HVEM contribute to ocular HSV reactivation. Our progress during the current funding
period has provided novel insights into potential mechanisms by which LAT regulation of HVEM expression
defines the extent of latency-reactivation and eye disease. Based on our data, we have formulated a bimodal
model in which the increased reactivation effects of sncRNA1&2 during latency are mediated by two different,
but inter-related, mechanisms: (i) sncRNA1&2 binding to the HVEM promoter leads to higher levels of HVEM
expression; and (ii) higher expression of HVEM enhances gD binding to HVEM and increases reactivation. We
will test our model using clinically relevant recombinant viruses in mouse models that control for the complexity
of the latent microenvironment in TG and its potential relationships with the primary infection as follows: (1)
Determine whether sncRNA1&2 are both required to upregulate HVEM and increase reactivation from
latency; and (2) Determine whether gD expression during latency and its binding to HVEM is required
for efficient reactivation from latency in TG of latently infected mice. Validation of this hypothetical model
will identify previously undescribed mechanisms that contribute to HSV-1 reactivation and will provide the
framework for identification of molecular targets and viral immune evasion response that could be exploited to
better manage latent HSV infection.
CLINICAL SIGNIFICANCE AND

## Key facts

- **NIH application ID:** 10833679
- **Project number:** 5R01EY029160-06
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** HOMAYON GHIASI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,500
- **Award type:** 5
- **Project period:** 2018-05-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833679

## Citation

> US National Institutes of Health, RePORTER application 10833679, Ocular HSV: Mechanism of virus reactivation (5R01EY029160-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10833679. Licensed CC0.

---

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