# Forward genetic prediction and testing of virulence loci in herpes simplex virus 1

> **NIH NIH R01** · PENNSYLVANIA STATE UNIVERSITY, THE · 2020 · $394,535

## Abstract

Project Summary
Herpes simplex virus 1 (HSV-1) and HSV-2 cause millions of chronic infections. These viruses cause
epithelial oral “cold” sores and genital lesions, which recur lifelong due to reactivation from a latent viral
reservoir in neurons. Clinical outcomes from HSV-1 infection are highly diverse, ranging from surface
lesions with quite different rates of recurrence, to asymptomatic shedding, to severe and potentially lethal
encephalitis. This variation is thought to be caused by a combination of factors, including viral genetic
differences, human genetic predisposition, and environmental variables. Animal models serve as the
cornerstone of our molecular understanding of HSV-1 disease in vivo, and provide an opportunity to
dissect viral genetic contributions to pathogenesis, while controlling for host genetic factors and
environmental variables.
We have recently sequenced a collection of low-passage clinical isolates of HSV-1 and categorized each
isolate according to its reproducible virulence phenotype in a mouse ocular model of infection. We
measured virulence in this model by the virus' ability to infect, replicate, and induce lethal disease, which
involved the virus initiating infection at the ocular surface, migrating to the peripheral nervous system
(trigeminal ganglia), and even penetrating into the central nervous system (CNS). Using multiple
statistical approaches, we found two loci in the viral tegument protein VP22 (UL49) that predictably
distinguish high-virulence clinical isolates from low-virulence isolates. VP22 is a viral tegument protein
that is conserved among alpha-herpesviruses, which functions as a hub of viral and cellular protein
interactions. VP22 functions in close concert with the viral transactivator protein VP16 (UL48), and the
viral RNAse VHS (UL41). The variant loci detected in association with murine virulence exist at a
frequency of approximately 50% in the clinical HSV-1 isolates we have surveyed to date, suggesting that
knowledge gleaned from these experiments will provide data on viral variants of relevance to ongoing
trials for antivirals and vaccines.
With increased power from additional genotype-phenotype data, we will use a genome-wide association
study (GWAS) to measure the association of VP22 and other candidate loci with virulence in HSV-1. We
will make recombinant HSV-1 strains to test the role(s) of VP22 and other candidate virulence loci both in
vivo and in vitro. We will test the hypothesis that virulent and non-virulent phenotypes in vivo result from
distinct biochemical differences in VP22 between these isolates. Data from these experiments will enable
us to test the robustness of our forward genetic predictions of virulence loci in HSV-1. If these data can
be linked to human impacts in the future, the ability to gauge likely virulence level based on viral
genotype would provide a powerful tool for future diagnostics and prediction of clinical outcomes.

## Key facts

- **NIH application ID:** 9851807
- **Project number:** 5R01AI132692-03
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** MORIAH SZPARA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,535
- **Award type:** 5
- **Project period:** 2018-02-23 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851807

## Citation

> US National Institutes of Health, RePORTER application 9851807, Forward genetic prediction and testing of virulence loci in herpes simplex virus 1 (5R01AI132692-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851807. Licensed CC0.

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