# Viral-host interactions that influence the life cycle of DNA tumor viruses

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $347,155

## Abstract

Project 2
Project Summary Abstract
Oncogenic viruses cause 15-20% of human cancers. High-risk HPVs are associated with 5% of cancers,
including cervical cancer (CC) as well as an increasing number of oropharyngeal squamous cell carcinomas
(OSCC). RNA molecules, such as long non-coding RNAs (lncRNAs) and co-transcriptional R-loops (RNA:DNA
hybrids) are associated with genomic instability and other hallmarks of cancer, but are understudied in the
context of HPV infection. Our preliminary data indicate high-risk HPV31 positive cells have increased levels of
R-loops compared to uninfected cells. Furthermore, we have identified several lncRNAs that are altered by
HPV31 that influence epithelial differentiation, proliferation and survival. Whether these RNA molecules serve a
pro-viral role and/or contribute to HPV pathogenesis is unclear. The DNA tumor viruses EBV and KSHV are also
found in the oral cavity and cause oral cancers. Similarly to HPV, EBV and KSHV also use differentiation of the
oral epithelium as a mechanism to activate lytic replication and virus production. Oral epithelial cells are the likely
source of infectious virus in the saliva and a critical component of viral pathogenesis. However, the mechanisms
that regulate the productive replication of HPV, as well as the latent/lytic phases of EBV and KSHV in the oral
epithelium are not well characterized. These viruses likely employ similar strategies to uncouple proliferation
from differentiation to promote both viral persistence and viral spread. KSHV and EBV alter the host lncRNA
profile in other cell types, and R-loop forming sequences have been identified in KSHV and EBV viral genomes.
Additionally, we have found that KSHV induces R-loop formation and DNA damage in oral epithelial cells. We
hypothesize that HPV, EBV and KSHV reprogram the epithelial cell environment through R-loop
formation/distribution and lncRNA expression in order to support the viral life cycle. Specific Aims to test this
hypothesis are: (1) Determine the role of R-loops in HPV and KSHV pathogenesis by mapping R-loop distribution
on cellular and viral DNA and determining if R-loops contribute to DNA damage in infected cells; (2) Determine
how cellular lncRNAs contribute to the life cycle of HPV as well as KSHV and EBV in epithelial cells through a
biased approach of overexpression/depletion studies of specific lncRNAs, and an unbiased approach through
high throughput sequencing to examine global alterations in lncRNA expression. Understanding how R-loops
and lncRNAs contribute to replication of these DNA tumor viruses may uncover a role for RNA molecules in
facilitating viral persistence as well as identify cellular pathways that may be exploited for the treatment of viral-
and potentially non-viral-associated cancers.

## Key facts

- **NIH application ID:** 10852901
- **Project number:** 5P01CA019014-44
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** CARY A MOODY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $347,155
- **Award type:** 5
- **Project period:** 1997-05-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852901

## Citation

> US National Institutes of Health, RePORTER application 10852901, Viral-host interactions that influence the life cycle of DNA tumor viruses (5P01CA019014-44). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10852901. Licensed CC0.

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