Epstein-Barr Virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are the leading cause of cancer in HIV-infected individuals and recent epidemiologic data suggests that these cancers are occurring in increased frequency in patients treated with combination antiretroviral treatment (cART). The underlying rationale of this program is that viral and host long noncoding RNAs play a role in gamma-herpesvirus pathogenesis and tuomorigenesis. Recent investigations into the function of human lncRNA have begun to illustrate how central this class of RNAs is to an array of cell regulatory processes such as gene silencing, transcriptional activation, gene imprinting, RNA maturation, splicing, etc. Based on our recent EBV transcriptomics work, we believe that there are likely scores of novel viral lncRNAs (vlncRNAs) expressed in different stages of the EBV infection cycle. Collaborative efforts with the Renne and Tibbetts labs to globally identify and resolve viral transcript structures are similarly uncovering dozens of novel non-coding KSHV and MHV68 RNAs revealing common themes such as vlncRNAs that can act as microRNA sponges and latency gene antisense transcripts that potentially contribute to the regulation of latency and reactivation, two steps that are crucial for virus biology and pathogenesis. In Project 2, we will investigate the functions of three distinct vlncRNA types expressed from the oncogenic latency membrane protein LMP2 locus, the protein product of which is required for growth transformation of primary human B cells. One of these vlncRNAs is antisense to LMP2 and is an apparent counterpart of the KSHV LAMP antisense transcript being investigated in Project 1. We will also investigate a series of unique sense oriented LMP2 isoforms. This includes chimeric LMP2 transcripts harboring exons from the transforming latency vlncRNA, RPMS1 (a BamHI A Rightward Transcript (BART) isoform), as well as a circular form of LMP2. We hypothesize that these LMP2 transcripts have diverse functions ranging from chromatin remodeling to interactions with B-cell receptor signaling pathways in both reactivation and possibly de novo infection and growth transformation. Importantly, Project 2 will exploit EBV's ability to growth transform B-lymphocytes to directly address the roles of both vlncRNAs and EBV regulated cellular lncRNAs in B-cell activation and in HIV-associated lymphomas, complementing similar investigations being pursued in Projects 1 and 3.

Public Health Relevance

The Epstein Barr virus is an etiological agent in most HIV/AIDS associated lymphomas. Previous investigations into the role of EBV genes in the establishment and maintenance of infection and in oncogenesis have focused primarily on protein coding genes. Recent studies, however, have revealed that EBV encodes dozens of viral long non-coding RNAs (vlncRNAs). Here we begin investigations into this newly appreciated group of viral transcripts through studying a set of structurally diverse vlncRNAs expressed from the latency LMP2 locus during reactivation and new infection. Preliminary studies suggest that they play roles in virus reactivation through multiple mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA214091-03
Application #
9648126
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Sethuraman, Sunantha; Gay, Lauren Appleby; Jain, Vaibhav et al. (2017) microRNA dependent and independent deregulation of long non-coding RNAs by an oncogenic herpesvirus. PLoS Pathog 13:e1006508
Zhang, Wensheng; Edwards, Andrea; Flemington, Erik K et al. (2017) Racial disparities in patient survival and tumor mutation burden, and the association between tumor mutation burden and cancer incidence rate. Sci Rep 7:13639