# HCMV receptors, signaling and entry

> **NIH NIH R56** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $531,685

## Abstract

PROJECT SUMMARY/ABSTRACT
Human cytomegalovirus (HCMV) is the leading infectious cause of birth defects in infants. HCMV can also cause
a variety of severe diseases in immunocompromised individuals. Mounting evidence have linked HCMV
infections to some cancers, most notably malignant glioma. Major progress has been made during the last
decade in understanding the molecular mechanism of viral entry and replication. A variety of host receptors and
signaling molecules have been shown to regulate HCMV infection. Recently, we used a CRISPR/Cas9 gene
editing based screening strategy to search for cellular proteins that are required for HCMV infection of epithelial
cells. We found that silencing the expression of an orphan olfactory receptor, OR14I1, drastically reduced HCMV
infection in these cells. Further work showed that OR14I1 interacts with the HCMV Pentamer complex (PC).
Together with additional evidence, we confirmed that OR14I1 is an HCMV receptor and may play critical role in
defining PC-dependent tropism. Despite the progress of identification of several host receptors for HCMV, there
are several critical gaps in our current knowledge of the molecular mechanism of viral entry and subsequent viral
life cycle. Specifically, it is unclear how HCMV uses multiple host receptors for entry and how virus subvert host
cellular signaling pathways facilitate viral replication and spreading. Our long-term goals are to identify how
HCMV uses normal host cellular processes to facilitate viral infection, to elucidate the entry mechanism related
to viral tropism, define the entry signaling pathways, and trafficking of HCMV to the nucleus by clarifying the
roles of OR14I1 and other receptors associated with its broad tropism and pathogenesis. Building on the past
work of our group and others, we propose to conduct research on three Specific Aims to address these goal: (1)
To elucidate the signaling pathways activated by HCMV-OR14I1 binding and their roles in virus infection and
uncover the role OR14I1 plays in cell-cell spread and trafficking; (2) To determine the contribution of different
HCMV PC receptors to infection and tropism; and (3) determine the structure of HCMV PC-OR14I1 and
determine relevant molecular interactions. Collectively, our proposed research will broadly impact the field by
characterizing the essential roles that host receptors, in particular, OR14I1, play in promoting viral entry,
replication, and spreading. These studies will have the potential to uncover novel molecular mechanisms
underlying HCMV infection, and molecular targets for HCMV therapy.

## Key facts

- **NIH application ID:** 10669505
- **Project number:** 1R56AI159672-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** TIMOTHY F KOWALIK
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $531,685
- **Award type:** 1
- **Project period:** 2022-09-06 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10669505

## Citation

> US National Institutes of Health, RePORTER application 10669505, HCMV receptors, signaling and entry (1R56AI159672-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10669505. Licensed CC0.

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