# HCMV stimulation of interferon signaling to promote viral gene expression and latency

> **NIH NIH F32** · UNIVERSITY OF ARIZONA · 2024 · $43,437

## Abstract

Project Summary
Human cytomegalovirus (HCMV) is a ubiquitous and medically significant pathogen which causes severe
morbidity and mortality among immunocompromised populations. HCMV, a betaherpesvirus, enters lifelong
quiescent persistence in the infected host known as latency. Latency is very complex but is known to require
the participation of both host and viral factors, and inhibition of either can lead to a loss of latency in ex vivo
model systems. HCMV specifically co-opts innate cellular antiviral signaling via the interferon alpha receptor
(IFNAR) signaling pathway, which leads to the activation of signal transducer and activator of transcription 1
(STAT1). STAT1 acts as a transcription factor, binding to a conserved DNA motif known as an interferon-
stimulated response element (ISRE) and initiating transcription of interferon stimulated genes (ISGs) which are
essential for antiviral defense. During normal cellular homeostasis, activated STAT1 (pSTAT1) is rapidly
dephosphorylated resulting in cessation of signaling, however, HCMV maintains STAT1 phosphorylation at
high levels through 72 hours. Maintenance of pSTAT1 during infection requires the viral protein UL138 in
complex with host UAF1 and USP1, and inhibition of these proteins prevents the establishment of latency,
suggesting that pSTAT1 signaling is essential for viral persistence. HCMV also appropriates pSTAT1 by
recruiting it to the viral genome, where it binds to viral ISRE sequences, suggesting the existence of viral ISGs.
In this proposal we seek to determine the mechanisms by which HCMV maintains STAT1 phosphorylation
during infection and the impacts of this prolonged signaling on viral replication and latency. We hypothesize
that HCMV manipulates the IFNAR1 signaling pathway to phosphorylate STAT1, thereby inducing transcription
of viral genes and promoting viral latency. Our goal is to answer two overarching questions. First, how does
HCMV maintain STAT1 signaling? We hypothesize that HCMV licenses STAT1 interaction with IFNAR by
removing inhibitory ubiquitin moieties, while simultaneously impeding sorting endosome turnover to prolong
IFNAR complex stability and signaling. Second, what is the impact of UL138-induced STAT1 signaling? We
hypothesize that STAT1 signaling is used by HCMV to regulate transcription of its own genes and to alter the
intracellular environment to promote latency. Answering these questions will provide new insight into viral and
cellular processes involved in the pathogenesis of this important human pathogen and potentially lead to novel
approaches to therapeutic or curative treatments.

## Key facts

- **NIH application ID:** 10995193
- **Project number:** 1F32AI186281-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Timothy M White
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,437
- **Award type:** 1
- **Project period:** 2024-11-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995193

## Citation

> US National Institutes of Health, RePORTER application 10995193, HCMV stimulation of interferon signaling to promote viral gene expression and latency (1F32AI186281-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10995193. Licensed CC0.

---

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