MicroRNAs are small non-coding regulatory RNA molecules that bind to 3'UTRs of mRNAs to either prevent their translation or induce their degradation. Previously identified in a variety of organisms ranging from plants to mammals, miRNAs are also now known to be produced by DNA viruses. The human ?-herpesvirus Epstein-Barr Virus has been shown to encode miRNAs which potentially regulate both viral and cellular genes. To determine whether Kaposi's Sarcoma-associated herpesvirus (KSHV) encodes miRNAs, we cloned small RNAs from KSHV positive primary effusion lymphoma derived cells. Sequence analysis revealed 11 isolated RNAs of 19 to 23 bases in length that perfectly align to KSHV. Surprisingly, all candidate miRNAs mapped to a single genomic locale within the latency-associated region of KSHV (Samols et al., Journal of Virology 2005). While our work was in review, two other laboratories reported the identification of KSHV-encoded miRNAs. Hence, these data suggest that virally-encoded miRNAs represent a novel mechanism by which KSHV may regulate viral and/or cellular gene expression during both latent and lytic KSHV replication. In human cells, over 450 miRNAs have been identified. Targets and functions of only a few miRNAs have been experimentally determined thus far, yet some miRNAs such as human hsa-miR-14 and hsa-miR-181 regulate fundamental biological processes like apoptosis, cell proliferation, and hematopoiesis and very recently have been implicated in tumorigenesis. Based on our preliminary results we hypothesize that miRNAs play an important role in the KSHV life cycle and may contribute to KSHV pathogenesis. To directly address this hypothesis we propose the following specific aims: SA1: Analysis of KSHV miRNA expression during latent and lytic replication in cultured cells and tissues samples of different origins. SA2: Identification of cellular and viral targets regulated by KSHV-encoded miRNAs. SA3: Evaluate the role of miRNA expression in the context of the viral genome. In support of our hypothesis we provide new preliminary data on identifying cellular miRNA targets in stably miRNA-expressing 293 cells (Samols et al., PLoS Pathogens, 2007, May 11). In summary, the identification of virally encoded miRNAs within the latency-associated region of KSHV is novel and very exciting as it suggests an entirely new level of regulating gene expression by which KSHV can potentially reprogram the host cell environment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AARR-C (04))
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
Verma, Dinesh; Li, Da-Jiang; Krueger, Brian et al. (2015) Identification of the physiological gene targets of the essential lytic replicative Kaposi's sarcoma-associated herpesvirus ORF57 protein. J Virol 89:1688-702
Feldman, Emily R; Kara, Mehmet; Coleman, Carrie B et al. (2014) Virus-encoded microRNAs facilitate gammaherpesvirus latency and pathogenesis in vivo. MBio 5:e00981-14
Haecker, Irina; Renne, Rolf (2014) HITS-CLIP and PAR-CLIP advance viral miRNA targetome analysis. Crit Rev Eukaryot Gene Expr 24:101-16
Yang, Yajie; Boss, Isaac W; McIntyre, Lauren M et al. (2014) A systems biology approach identified different regulatory networks targeted by KSHV miR-K12-11 in B cells and endothelial cells. BMC Genomics 15:668
Reese, T A; Wakeman, B S; Choi, H S et al. (2014) Helminth infection reactivates latent ?-herpesvirus via cytokine competition at a viral promoter. Science 345:573-7
Plaisance-Bonstaff, Karlie; Choi, Hong Seok; Beals, Tyler et al. (2014) KSHV miRNAs decrease expression of lytic genes in latently infected PEL and endothelial cells by targeting host transcription factors. Viruses 6:4005-23
Zhu, Ying; Haecker, Irina; Yang, Yajie et al. (2013) ?-Herpesvirus-encoded miRNAs and their roles in viral biology and pathogenesis. Curr Opin Virol 3:266-75
Han, Soo-Jin; Marshall, Vickie; Barsov, Eugene et al. (2013) Kaposi's sarcoma-associated herpesvirus microRNA single-nucleotide polymorphisms identified in clinical samples can affect microRNA processing, level of expression, and silencing activity. J Virol 87:12237-48
Boss, Isaac W; Renne, Rolf (2011) Viral miRNAs and immune evasion. Biochim Biophys Acta 1809:708-14
Boss, Isaac W; Nadeau, Peter E; Abbott, Jeffrey R et al. (2011) A Kaposi's sarcoma-associated herpesvirus-encoded ortholog of microRNA miR-155 induces human splenic B-cell expansion in NOD/LtSz-scid IL2Rýýnull mice. J Virol 85:9877-86

Showing the most recent 10 out of 14 publications