# "Project 3" Defining the in vivo function of ncRNAs during MHV68 latency and lymphomagenesis

> **NIH NIH P01** · UNIVERSITY OF FLORIDA · 2024 · $76,753

## Abstract

Project Summary
The transforming human gammaherpesviruses EBV and KSHV establish stable latent infections in B cells, 
providing a lifelong reservoir of virus that can contribute to the development of malignant disease. Thus, defining 
the mechanisms that govern long-term latency and tumorigenesis is critical for designing rational strategies to 
prevent disease. In vivo studies of gammaherpesviruses in humans have been severely limited by the difficulties 
of working in the natural host. Murine gammaherpesvirus 68 (MHV68) is related to EBV and KSHV and causes 
lymphomas and lymphoproliferative disease in mice, providing a readily manipulatable small animal model for 
mechanistic studies of the virus/host relationship in vivo. Like EBV and KSHV, MHV68 expresses multiple forms 
of ncRNAs whose functions during infection and pathogenesis are largely unknown. In contrast to most 
gammaherpesvirus protein-coding genes, gammaherpesvirus ncRNAs are abundantly expressed in vivo during 
chronic infection and in hyperplastic lesions during lymphoproliferative disease, suggesting that these ncRNAs 
may play key conserved roles in latency and tumorigenesis. In support of this, we have demonstrated that 
MHV68 TMER4 and EBV EBER1 share a conserved function in hematogenous dissemination, and that in vivo
suppression of a conserved miRNA target promotes B cell latency. Further, our new preliminary findings implicate 
both small ncRNAs and miRNAs in the genesis and progression of virus-induced B cell lymphoma. Thus, we 
hypothesize that gammaherpesviruses utilize a broad array of ncRNAs to shape critical B cell signaling pathways 
and thereby promote virus dissemination, latency and tumorigenesis. In Aim 1 (in collaboration with Project 2
and with support from Cores C and D), we will define the mechanisms by which gammaherpesvirus small RNAs 
promote the egress and dissemination of infected B cells, facilitate B cell latency at peripheral sites, and drive 
key stages of lymphomagenesis. In Aim 2 (in collaboration with Projects 2 and 3, and with support from Cores 
B, C and D) we will define the contribution of gammaherpesvirus miRNA repression of host mRNAs and lncRNAs 
to B cell latency and lymphomagenesis. The highly collaborative nature of this program, along with the systematic 
in vivo analyses of ncRNA mutants and recombinant viruses carrying EBV or KSHV genes, provides an 
extremely powerful means to determine the specific molecular mechanisms by which ncRNAs contribute to 
gammaherpesvirus latency and tumorigenesis.

## Key facts

- **NIH application ID:** 11140082
- **Project number:** 3P01CA214091-08S2
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Scott A. Tibbetts
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,753
- **Award type:** 3
- **Project period:** 2017-02-09 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11140082

## Citation

> US National Institutes of Health, RePORTER application 11140082, "Project 3" Defining the in vivo function of ncRNAs during MHV68 latency and lymphomagenesis (3P01CA214091-08S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11140082. Licensed CC0.

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