# Ocular HSV: Mechanism of virus reactivation

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $425,000

## Abstract

Project Summary
Following primary ocular HSV-1 infection, the virus replicates in the eye and establishes latency in the
trigeminal ganglia (TG). In a latently infected individual, the virus can occasionally reactivate and travel back to
the eye causing recurrent disease. Reactivation from latency is the major cause of eye disease. However, the
mechanisms underlying this process are not well defined, and currently it is not clear whether reactivation
reflects a failure in latency mechanisms or independent mechanisms that break latency. It is well established
that the continued expression of the HSV-1 Latency Associated Transcript (LAT) is a characteristic of latency,
and this is associated with suppression of apoptosis and regulation of T cell responses to the infected sensory
neurons. Recently, we found that in the TG of mice infected with LAT(-) virus, the levels of the HSV-1 receptor,
HVEM, but not other HSV-1 receptors was significantly down-regulated. Furthermore, HSV-1 latency and
reactivation were reduced significantly in HVEM-/- mice as compared to wild-type mice. Notably, the LAT
function in upregulating HVEM mapped to two recently described small non-coding LAT RNAs (sncRNA1 and
2), since HVEM was upregulated following transient transfection with plasmids expressing either small non-
coding RNA. In parallel, we have found that viral glycoprotein gD, capable of binding HVEM and triggering its
signaling through NF-κB, is expressed at low levels in latently infected TG. Collectively, our preliminary data
provide compelling evidence supporting the hypothesis that LAT can enhance latency-reactivation and T-cell
exhaustion by upregulating HVEM, which in turn promotes HSV-1 reactivation, possibly by facilitating the
binding of gD to HVEM. Although the LAT(-) virus expressing baculovirus inhibitor of apoptosis protein gene
(cpIAP) had similar levels of latency as wild-type LAT(+) virus, this recombinant virus did not increase HVEM
levels suggesting that this reactivation mechanism does not promote reactivation by regulating responsiveness
to apoptosis. Rather, this mechanism appears to interfere with the ability of LAT to promote immune evasion.
We propose to test this hypothesis using in vivo analyses of engineered recombinant viruses to: (1) Test
whether binding of HSV-1 gD to HVEM is required for efficient reactivation in TG of latently infected
mice; and (2) Test whether the LAT sncRNAs upregulate HVEM by binding to the HVEM promoter.
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:** 9942463
- **Project number:** 5R01EY029160-03
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** HOMAYON GHIASI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,000
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942463

## Citation

> US National Institutes of Health, RePORTER application 9942463, Ocular HSV: Mechanism of virus reactivation (5R01EY029160-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9942463. Licensed CC0.

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