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J Virol. 2019 Mar 5;93(6). pii: e01952-18. doi: 10.1128/JVI.01952-18. Print 2019 Mar 15.

Comparative Analysis of Gammaherpesvirus Circular RNA Repertoires: Conserved and Unique Viral Circular RNAs.

Author information

1
Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, USA.
2
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida, USA.
3
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
4
Department of Microbiology and Immunology, Tulane Regional Primate Center, Covington, Louisiana, USA.
5
Division of Comparative Pathology, Tulane Regional Primate Center, Covington, Louisiana, USA.
6
Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
7
Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa, USA.
8
Reprocell USA, Beltsville, Maryland, USA.
9
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, USA.
10
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA stibbe@ufl.edu erik@tulane.edu.
11
Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana, USA stibbe@ufl.edu erik@tulane.edu.
#
Contributed equally

Abstract

Recent studies have identified circular RNAs (circRNAs) expressed from the Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) human DNA tumor viruses. To gain initial insights into the potential relevance of EBV circRNAs in virus biology and disease, we assessed the circRNAome of the interspecies homologue rhesus macaque lymphocryptovirus (rLCV) in a naturally occurring lymphoma from a simian immunodeficiency virus (SIV)-infected rhesus macaque. This analysis revealed rLCV orthologues of the latency-associated EBV circular RNAs circRPMS1_E4_E3a and circEBNA_U. Also identified in two samples displaying unusually high lytic gene expression was a novel rLCV circRNA that contains both conserved and rLCV-specific RPMS1 exons and whose backsplice junctions flank an rLCV lytic origin of replication (OriLyt). Analysis of a lytic infection model for the murid herpesvirus 68 (MHV68) rhadinovirus identified a cluster of circRNAs near an MHV68 lytic origin of replication, with the most abundant of these, circM11_ORF69, spanning the OriLyt. Lastly, analysis of KSHV latency and reactivation models revealed the latency associated circRNA originating from the vIRF4 gene as the predominant viral circRNA. Together, the results of this study broaden our appreciation for circRNA repertoires in the Lymphocryptovirus and Rhadinovirus genera of gammaherpesviruses and provide evolutionary support for viral circRNA functions in latency and viral replication.IMPORTANCE Infection with oncogenic gammaherpesviruses leads to long-term viral persistence through a dynamic interplay between the virus and the host immune system. Critical for remodeling of the host cell environment after the immune responses are viral noncoding RNAs that modulate host signaling pathways without attracting adaptive immune recognition. Despite the importance of noncoding RNAs in persistent infection, the circRNA class of noncoding RNAs has only recently been identified in gammaherpesviruses. Accordingly, their roles in virus infection and associated oncogenesis are unknown. Here we report evolutionary conservation of EBV-encoded circRNAs determined by assessing the circRNAome in rLCV-infected lymphomas from an SIV-infected rhesus macaque, and we report latent and lytic circRNAs from KSHV and MHV68. These experiments demonstrate utilization of the circular RNA class of RNAs across 4 members of the gammaherpesvirus subfamily, and they identify orthologues and potential homoplastic circRNAs, implying conserved circRNA functions in virus biology and associated malignancies.

KEYWORDS:

EBV; Epstein-Barr virus; KSHV; Kaposi’s sarcoma herpesvirus; MHV68; circRNA; circular RNA; lymphocryptovirus; murid herpesvirus 68; rhadinovirus

PMID:
30567979
PMCID:
PMC6401440
[Available on 2019-09-05]
DOI:
10.1128/JVI.01952-18

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