# Circular RNAs in HSV1 infection and antiviral immunity

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $52,288

## Abstract

Project Summary
Circular (circ) RNAs are a recently described class of RNAs generated by backsplicing of adjacent exons,
whose expression is altered in several disease states and some of the few viral infections in which they have
been studied. Functionally, circRNAs rarely direct protein synthesis but have been linked to the sequestration
of microRNAs and RNA binding proteins (RNA-BPs). CircRNAs were recently implicated in controlling the
activation of double-stranded (ds) RNA-activated eIF2α kinase PKR by providing an abundant pool of inhibitory
short duplex RNA sequences. Bound inactive PKR can be rapidly mobilized by if RNase L is activated,
resulting in endoribonucleolytic cleavage of circRNAs. Generated by both RNA virus replication and dsDNA
virus transcription from opposing genome strands, dsRNA is a potent pathogen associated molecular pattern
(PAMP) whose recognition by PKR and the OAS/RNase L pathway leads to an abrupt defensive shutdown of
mRNA translation to thwart viral protein synthesis. In addition to possible virus and circRNA -specific
interactions, the potential of circRNAs to calibrate dsRNA responses therefore suggests a broad significance to
virus biology. However, precisely how the infected cell circRNA population responds to herpes simplex type 1
(HSV1) infection and impacts virus reproduction remains unknown and represents a significant knowledge gap.
The overall goal of this proposal is to understand how circRNAs contribute to HSV1 infection and
antiviral immunity. Our preliminary data in HSV1-infected cells indicate that circRNAs are protected from
degradation by the viral endoribonuclease vhs and are in fact selectively upregulated through a mechanism
dependent on the viral immediate early protein ICP27. We also find that PKR activation is dependent on
RNase L function, suggesting that circRNAs are important inhibitors of PKR in HSV1 infection that must be
degraded for a full antiviral response. These data are consistent with the novel hypothesis that HSV1 actively
manipulates this class of host RNAs to evade cell intrinsic antiviral defenses and preserve protein synthesis
and viral replication. This proposal will be divided into two aims to fully understand 1) how HSV1 shapes the
infected cell circRNAome and 2) the functional impact of these alterations. These studies will reveal how
circRNAs are manipulated by HSV1 and their importance in infection and immunity to a medically important
human pathogen. Ultimately, this work could lead to new strategies for treating a wide variety of viral infections
and have significant implications for our understanding of infection, host defenses and circRNA biology.

## Key facts

- **NIH application ID:** 10354703
- **Project number:** 1R21AI166638-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Hannah Marion Burgess
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $52,288
- **Award type:** 1
- **Project period:** 2021-09-24 → 2022-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354703

## Citation

> US National Institutes of Health, RePORTER application 10354703, Circular RNAs in HSV1 infection and antiviral immunity (1R21AI166638-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10354703. Licensed CC0.

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