# Project 4: Regulation of EBV Latency and Oncogenesis by Hypoxia

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $459,296

## Abstract

Abstract:
Epstein-Barr Virus (EBV) a human gammaherpesvirus that is associated with diverse lymphoid and epithelial
malignancies. Like all cancers, EBV-associated cancers must compete and survive in nutrient depleted
environments. Adaptation to oxygen fluctuation is a hallmark of most cancers. In this proposal, we investigate
how oxygen metabolism plays a central role in EBV latency and tumorigenesis. For aim 1, we will investigate
how EBV modulates the host hypoxic response during primary infection. Our preliminary data indicates EBNA1
and EBNA2 can bind and regulate cellular genes controlling the hypoxic response, including hypoxia inducible
factor 1 alpha (HIF1A). We will test the hypothesis that EBV infection modulates the host response to hypoxia
to promote infected cell survival and promote tumorigenesis. For aim 2, we will investigate how the viral
epigenome is regulated by oxygen sensing enzymes. EBV associated Burkitt lymphoma (BL) and epithelial
malignancies are known to acquire high DNA methylation commonly referred to as the CpG island methylator
phenotype (CIMP). We will investigate how DNA methylation is regulated through the oxygen-sensitive control
of TET2 enzymes and explore how hypoxia contributes to CIMP and silencing of tumor suppressor genes. For
aim 3, we will test how oxygen sensing enzymes regulate EBNA1 and EBV episome maintenance during latency.
We have found that proline and lysine hydroxylases regulate EBNA1 and EBNA2 protein stability and function.
We have mapped interaction sites on EBNA1 that bind the lysine hydroxylase PLOD1 and found this interaction
essential for EBNA1 protein stability under normoxia. We now propose to investigate how hypoxia regulates the
interaction of PLOD1 with EBNA1 to control EBV episome maintenance and persistence during latent infection.
These aims are highly integrated with other members of the program project exploring hypoxia effects on related
tumor viruses. Together, these aims will provide a framework to understand how viruses respond to hypoxia to
promote host cell survival and drive the oncogenic process.

## Key facts

- **NIH application ID:** 10914924
- **Project number:** 5P01CA281867-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** PAUL M. LIEBERMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,296
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914924

## Citation

> US National Institutes of Health, RePORTER application 10914924, Project 4: Regulation of EBV Latency and Oncogenesis by Hypoxia (5P01CA281867-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10914924. Licensed CC0.

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