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Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):12805-12810. doi: 10.1073/pnas.1816183115. Epub 2018 Nov 19.

Discovery of Kaposi's sarcoma herpesvirus-encoded circular RNAs and a human antiviral circular RNA.

Author information

1
HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
2
Thoracic and Gastrointestinal (GI) Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
3
Collaborative Bioinformatics Resource, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
4
Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, Bethesda, MD 20894.
5
HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; ziegelbauerjm@mail.nih.gov.

Abstract

Noncoding RNAs have substantial effects in host-virus interactions. Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs which can decoy other RNAs or RNA-binding proteins to inhibit their functions. The role of circRNAs is largely unknown in the context of Kaposi's sarcoma herpesvirus (KSHV). We hypothesized that circRNAs influence viral infection by inhibiting host and/or viral factors. Transcriptome analysis of KSHV-infected primary endothelial cells and a B cell line identified human circRNAs that are differentially regulated upon infection. We confirmed the expression changes with divergent PCR primers and RNase R treatment of specific circRNAs. Ectopic expression of hsa_circ_0001400, a circRNA induced by infection, suppressed expression of key viral latent gene LANA and lytic gene RTA in KSHV de novo infections. Since human herpesviruses express noncoding RNAs like microRNAs, we searched for viral circRNAs encoded in the KSHV genome. We performed circRNA-Seq analysis with RNase R-treated, circRNA-enriched RNA from KSHV-infected cells. We identified multiple circRNAs encoded by the KSHV genome that are expressed in KSHV-infected endothelial cells and primary effusion lymphoma (PEL) cells. The KSHV circRNAs are located within ORFs of viral lytic genes, are up-regulated upon the induction of the lytic cycle, and alter cell growth. Viral circRNAs were also detected in lymph nodes from patients of KSHV-driven diseases such as PEL, Kaposi's sarcoma, and multicentric Castleman's disease. We revealed new host-virus interactions of circRNAs: human antiviral circRNAs are activated in response to KSHV infection, and viral circRNA expression is induced in the lytic phase of infection.

KEYWORDS:

KSHV; circRNA-Seq; circular RNA; herpesvirus; noncoding RNA

Comment in

PMID:
30455306
PMCID:
PMC6294913
DOI:
10.1073/pnas.1816183115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: T.S.U. is a coinventor on a patent application related to the treatment of KSHV-associated diseases with pomalidomide. This invention was made as part of his duties as an employee of the US government, and the patents are or will be assigned to the US Department of Health and Human Services. The government may convey a portion of the royalties it receives from licensure of its patents to its employee inventors. T.S.U. has recently conducted clinical research using drugs supplied to the National Cancer Institute through cooperative research and development agreements with Celgene Corp., Merck and Co., and Hoffman LaRoche.

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