# Restriction of KSHV by cellular RNA decay pathways

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $400,313

## Abstract

Project Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the subfamily gammaherpesvirinae and is
causally associated with the development of several malignancies including Kaposi’s sarcoma and primary
effusion lymphoma (PEL). The virus’ ability to establish latency as well as reactivate are essential for the
development of KSHV-associated disease. Despite these requirements for disease progression there are
significant gaps in knowledge regarding cell-intrinsic mechanisms that restrict the KSHV lifecycle. While innate
restriction is typically thought of in the context of antiviral immune responses, growing evidence suggests that
cellular RNA quality control pathways have an antiviral role. Nonsense-mediated RNA decay (NMD) is an
evolutionarily conserved RNA decay pathway that facilitates degradation of RNAs on which ribosomes are
deemed to terminate translation aberrantly. Emerging evidence has pointed to a role for NMD in antiviral
restriction with a prominent role limiting replication of positive-stranded RNA viruses, however, a role for NMD in
DNA virus restriction, such as KSHV, was unknown. We recently reported the discovery that NMD is a cell-
intrinsic restriction mechanism for DNA viruses and demonstrated that it imposes a significant restriction on the
KSHV lifecycle in PEL cells. Our data demonstrate that NMD-dependent restriction is linked both to the regulation
of the unfolded protein response (UPR) as well as targeted degradation of the main KSHV transcription factor,
RTA. Building upon these observations our central hypothesis is that NMD restricts KSHV reactivation by
targeting key viral mRNAs as well as cellular transcripts in pathways important for viral gene expression and that
the virus antagonizes NMD through viral-encoded mechanisms. To test this hypothesis, we propose an
integrated series of experiments aimed at determining the interactions between NMD and KSHV. In Aim 1, we
will investigate how NMD-dependent regulation of the UPR pathway regulates the KSHV lifecycle. In Aim 2, we
will investigate a class of KSHV mRNAs that escape NMD despite harboring sequence features that should
render them NMD-susceptible. In Aim 3, we will determine the mechanism by which KSHV-encoded proteins
inhibit NMD. Completion of these studies is expected to determine how NMD restricts the KSHV lifecycle as well
as the mechanisms the virus employs to antagonize it. These will represent fundamental new insights into how
DNA virus infection is regulated by cell-intrinsic mechanisms and can be harnessed for the development of new
therapeutic strategies.

## Key facts

- **NIH application ID:** 10805505
- **Project number:** 5R01CA278642-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** John Karijolich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,313
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805505

## Citation

> US National Institutes of Health, RePORTER application 10805505, Restriction of KSHV by cellular RNA decay pathways (5R01CA278642-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10805505. Licensed CC0.

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