The unifying postulate of this P01 proposal is that comparative studies of KSHV, EBV, and MHV68 will accelerate the discovery of pathways regulated by long non-coding RNAs (lncRNAs) that contribute to gammaherpesvirus latency and tumorigenesis. Specifically, we hypothesize A) that herpesviruses utilize lncRNAs to regulate both virus and host gene expression, and B) that viral lncRNAs and/or virus-perturbed host lncRNAs directly contribute to the genesis of virus-associated AIDS malignancies. To address these hypotheses we propose three highly integrated projects with the goal of functionally analyzing lncRNAs and their mechanisms of action. Project 1, led by Dr. Renne (University of Florida, UF), will investigate KSHV- encoded lncRNAs and alteration of host lncRNA expression in the context of HIV-associated KSHV malignancies. Project 2, led by Dr. Flemington (Tulane University) will interrogate Epstein-Barr virus lncRNAs and alteration of host lncRNA expression in the context of HIV-associated EBV malignancies. Project 3 led by Dr. Tibbetts (UF) will investigate function of MHV68 lncRNAs and alteration of host lncRNAs in the context of latency and lymphomagenesis in a facile murine model. Importantly, all projects are supported by strong novel preliminary data, including the discovery of new gammaherpesvirus lncRNAs using a novel multi-platform genomics approach and implicating some of these lncRNAs in viral biology and pathogenesis. The well- organized Administrative core (Core A, Core Leader: Rolf Renne) will maintain oversight and organization of the program, including biostatisical consultation and adherence to reproducibility and transparency standards. Two additional service cores, which are already established and very productive, will support sequencing, bioinformatics and recombinant virus generation needs across the three projects: The Virus RNA-seq and Bioinformatics Core will be maintained at Tulane University (Core B, Core Leader: Erik Flemington). The Recombinant Virus Core, which was established with an NCI-funded RC2 award in 2009, will be maintained at UF (Core C, Core Leader: Rolf Renne). In addition, Dr. Parsons (LSUHSC, New Orleans), who leads the NIH- supported LSUHSC/LCRC HIV Clinical and Biospecimen Repository, will facilitate the acquisition of valuable Kaposi's sarcoma (KS) and lymphoma tumor specimens from HIV-infected patients. Our proposal is significant and highly innovative in terms of the field of study ? ?understanding virus and host lncRNA function in gammaherpesvirus tumorigenesis? ? and in applying numerous state-of-the-art techniques across all three projects. Finally, studying pathogenesis-relevant tissue culture and animal models, complemented by the analysis of human tumor tissues from EBV- and KSHV-associated malignancies, will greatly increase our understanding of both viral and host lncRNAs in the context of AIDS malignancies.

Public Health Relevance

The unifying postulate of this P01 proposal is that comparative studies of KSHV, EBV, and MHV68 will accelerate the discovery of pathways regulated by non-coding RNAs (ncRNAs) that contribute to gamma- herpesvirus tumorigenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (O2))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Schools of Medicine
United States
Zip Code
Van Skike, Nick D; Minkah, Nana K; Hogan, Chad H et al. (2018) Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice. PLoS Pathog 14:e1006843
Bullard, Whitney L; Flemington, Erik K; Renne, Rolf et al. (2018) Connivance, Complicity, or Collusion? The Role of Noncoding RNAs in Promoting Gammaherpesvirus Tumorigenesis. Trends Cancer 4:729-740
Sethuraman, Sunantha; Thomas, Merin; Gay, Lauren A et al. (2018) Computational analysis of ribonomics datasets identifies long non-coding RNA targets of ?-herpesviral miRNAs. Nucleic Acids Res 46:8574-8589
Jain, Vaibhav; Renne, Rolf (2018) Visualization of molecular biology: The LANA tether. Proc Natl Acad Sci U S A 115:4816-4818
Dai, Lu; Del Valle, Luis; Miley, Wendell et al. (2018) Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi's sarcoma development. Oncogene 37:4534-4545
Gay, Lauren A; Sethuraman, Sunantha; Thomas, Merin et al. (2018) Modified Cross-Linking, Ligation, and Sequencing of Hybrids (qCLASH) Identifies Kaposi's Sarcoma-Associated Herpesvirus MicroRNA Targets in Endothelial Cells. J Virol 92:
Mei, Suyu; Flemington, Erik K; Zhang, Kun (2018) Transferring knowledge of bacterial protein interaction networks to predict pathogen targeted human genes and immune signaling pathways: a case study on M. tuberculosis. BMC Genomics 19:505
Gay, Lauren A; Turner, Peter C; Renne, Rolf (2018) Contemporary Ribonomics Methods for Viral microRNA Target Analysis. Noncoding RNA 4:
Tonnessen-Murray, Crystal; Ungerleider, Nathan A; Rao, Sonia G et al. (2018) p53 Mediates Vast Gene Expression Changes That Contribute to Poor Chemotherapeutic Response in a Mouse Model of Breast Cancer. Transl Oncol 11:930-940
Zhang, Wensheng; Flemington, Erik K; Zhang, Kun (2018) Driver gene mutations based clustering of tumors: methods and applications. Bioinformatics 34:i404-i411

Showing the most recent 10 out of 27 publications