# Project 3 - Latent and Lytic EBV Infection in Epithelial Cells

> **NIH NIH P01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $422,828

## Abstract

PROJECT 3 – PROJECT SUMMARY/ABSTRACT
Project 3. Latent and Lytic EBV Infection in Epithelial Cells
Shannon Kenney, Project Leader; Eric Johannsen, Co-Leader
Epstein-Barr virus (EBV) is an important cause of human epithelial cell cancers, particularly undifferentiated
nasopharyngeal carcinoma (NPC), but the precise mechanism(s) by which latent EBV infection promotes NPCs
are poorly understood. EBV also induces oral hairy leukoplakia (OHL) lesions in the tongue epithelium of AIDS
patients, which is caused by completely lytic EBV infection in differentiated squamous epithelial cells. We
recently discovered that latent EBV infection inhibits differentiation, and promotes proliferation, of a telomerase-
immortalized normal oral keratinocyte cell line (NOKs), and that this effect is mediated by the latent EBV protein,
LMP1. Our exciting preliminary results show that LMP1 affects NOKs proliferation and differentiation by
activating the downstream targets of the Hippo tumor suppressive pathway, YAP and TAZ. Conversely, we have
discovered that the ability of EBV to enter lytic viral infection in NOKs is induced by cellular differentiation and
requires the differentiation-associated proteins, IRF6/RIPK4, as well as KLF4/BLIMP1/YAP/TAZ, although the
pathways that regulate lytic EBV reactivation during differentiation are not yet fully defined. In Project 4, a
collaboration between the Kenney and Johannsen labs, we will dissect how the latent EBV oncoprotein LMP1,
in conjunction with YAP/TAZ, inhibits epithelial cell differentiation and enhances proliferation (both key steps in
the pathway to tumor formation), and further define how lytic EBV reactivation is activated by differentiation-
dependent mechanisms in normal epithelial cells. In Aim 1, we will define how LMP1 activates YAP and TAZ,
and inhibits cellular differentiation, in NOKs. In Aim 2, we will identify novel cellular genes/pathways that drive or
inhibit lytic EBV in NOKs. In Aim 3, we will ask if FDA-approved drugs that inhibit or activate YAP/TAZ activity
block the growth of EBV+ epithelial cell tumors and/or regulate lytic EBV reactivation. We hypothesize that LMP1
inhibits differentiation by activating YAP and/or TAZ (Aim 1), that epithelial cell differentiation induces lytic EBV
reactivation at least partially though activation of the RIPK4/IRF6 axis (Aim 2), and that YAP/TAZ inhibitors will
impair the growth of EBV-infected NPCs
and gastric cancers
expressing LMP1 (Aim 3). This project involves
collaborations between multiple investigators, including Dr. Kenney, Dr. Johannsen and Dr. Lambert, and will
use multiple Cores, including the virus core, the microscopy core, and the administrative core.

## Key facts

- **NIH application ID:** 10837989
- **Project number:** 2P01CA022443-46A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Shannon Celeste Kenney
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $422,828
- **Award type:** 2
- **Project period:** 1997-02-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837989

## Citation

> US National Institutes of Health, RePORTER application 10837989, Project 3 - Latent and Lytic EBV Infection in Epithelial Cells (2P01CA022443-46A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10837989. Licensed CC0.

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