title: Japanese Macaque Rhadinovirus Encodes a Viral MicroRNA Mimic of the miR-17 Family.
abstract: Japanese macaque (JM) rhadinovirus (JMRV) is a novel, gamma-2 herpesvirus that was recently isolated from JM with inflammatory demyelinating encephalomyelitis (JME). JME is a spontaneous and chronic disease with clinical characteristics and immunohistopathology comparable to those of multiple sclerosis in humans. Little is known about the molecular biology of JMRV. Here, we sought to identify and characterize the small RNAs expressed during lytic JMRV infection using deep sequencing. Fifteen novel viral microRNAs (miRNAs) were identified in JMRV-infected fibroblasts, all of which were readily detectable by 24 h postinfection and accumulated to high levels by 72 h. Sequence comparisons to human Kaposi's sarcoma-associated herpesvirus (KSHV) miRNAs revealed several viral miRNA homologs. To functionally characterize JMRV miRNAs, we screened for their effects on nuclear factor kappa B (NF-κB) signaling in the presence of two proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Multiple JMRV miRNAs suppressed cytokine-induced NF-κB activation. One of these miRNAs, miR-J8, has seed sequence homology to members of the cellular miR-17/20/106 and miR-373 families, which are key players in cell cycle regulation as well as inflammation. Using reporters, we show that miR-J8 can target 3' untranslated regions (UTRs) with miR-17-5p or miR-20a cognate sites. Our studies implicate JMRV miRNAs in the suppression of innate antiviral immune responses, which is an emerging feature of many viral miRNAs.
  
  
  
  Gammaherpesviruses are associated with multiple diseases linked to immunosuppression and inflammation, including AIDS-related cancers and autoimmune diseases. JMRV is a recently identified herpesvirus that has been linked to JME, an inflammatory demyelinating disease in Japanese macaques that mimics multiple sclerosis. There are few large-animal models for gammaherpesvirus-associated pathogenesis. Here, we provide the first experimental evidence of JMRV miRNAs in vitro and demonstrate that one of these viral miRNAs can mimic the activity of the cellular miR-17/20/106 family. Our work provides unique insight into the roles of viral miRNAs during rhadinovirus infection and provides an important step toward understanding viral miRNA function in a nonhuman primate model system.
authors: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA skalsky@ohsu.edu.
authors: Rebecca L
authors: RL
authors: Skalsky
authors: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
authors: Sarah A
authors: SA
authors: Barr
authors: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
authors: Andrew J
authors: AJ
authors: Jeffery
authors: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
authors: Tiffany
authors: T
authors: Blair
authors: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
authors: Ryan
authors: R
authors: Estep
authors: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.
authors: Scott W
authors: SW
authors: Wong
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003711:Demyelinating Diseases / Q000235:genetics / Q000821:virology; D004679:Encephalomyelitis / Q000235:genetics / Q000821:virology; D020869:Gene Expression Profiling / Q000379:methods; D057809:HEK293 Cells; D006566:Herpesviridae Infections / Q000235:genetics / Q000821:virology; D019288:Herpesvirus 8, Human / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D007564:Japan; D008251:Macaca / Q000821:virology*; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics*; D018144:Rhadinovirus / Q000235:genetics*; D017385:Sequence Homology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D053583:Interleukin-1beta; D035683:MicroRNAs; D016328:NF-kappa B; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha