Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is etiologically linked to several human cancers, including AIDS-associated B-cell lymphomas. Previously, we have reported that both EBV-encoded microRNAs (miRNAs) and EBV-induced cellular miRNAs play a critical role in promoting cellular transformation by EBV in culture. Here, we propose an integrated series of experiments designed to lead to a mechanistic understanding of how the miRNAs encoded by, or induced by, EBV infection contribute to the growth and transformation of human cells in culture and in vivo. We will dissect the mechanisms used by EBV-encoded and EBV-induced cellular miRNAs to facilitate the formation of stably immortalized lymphoblastoid cell lines (LCLs) and, more generally, examine how miRNAs contribute to lymphomagenesis and control the decision between viral latency and lytic replication. In addition, we will determine whether specific viral or cellular miRNAs promote the growth and viability of latently EBV-infected diffuse large B cell lymphoma cells (DLBCLs) and nasopharyngeal carcinoma (NPC) cells, in order to ascertain whether EBV uses common mechanisms to transform B lymphocytes and epithelial cells. While one important focus of this grant will be on a cluster of three EBV-encoded miRNAs (miR-BHRF1-1, 1-2 and 1-3) that is expressed at high levels in LCLs and in many DLBCLs, we will also address how the 22-miRNA EBV BART cluster affects the ability of EBV-transformed cells to grow in culture and to avoid immune elimination. Critically, we will integrate miRNA target identification, using a powerful cross-linking and immunoprecipitation (CLIP) technique, with phenotypic studies of miRNA:mRNA interactions to define the mechanisms of action used by these miRNAs to mediate EBV latency and pathogenesis.

Public Health Relevance

Epstein-Barr virus (EBV) is a herpesvirus that is linked to several human diseases, including AIDS- associated B-cell lymphomas and nasopharyngeal carcinomas. We have observed that microRNAs, either those encoded by EBV itself or cellular microRNAs activated upon infection, play an important role in the establishment and/or maintenance of cellular transformation induced by EBV. This grant seeks to understand the mechanisms underlying this process with a view to the development of potential new treatment modalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067968-07
Application #
8471604
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Beisel, Christopher E
Project Start
2005-12-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$368,950
Indirect Cost
$133,950
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Jin, Hyun Yong; Oda, Hiroyo; Lai, Maoyi et al. (2013) MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways. EMBO J 32:2377-91

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