Regulation of the viral life cycle by murine gammaherpesvirus 68 microRNAs

Arch Virol. 2017 Mar;162(3):657-667. doi: 10.1007/s00705-016-3150-y. Epub 2016 Nov 11.

Abstract

γ-Herpesviruses (γHV) such as Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus are important human pathogens involved in lymphoproliferation and tumorigenesis. Murine gammaherpesvirus 68 (MHV-68, γHV-68) is an effective model for the study of γHV pathogenesis and host-virus interaction because it is closely related to human γHV. Similarly to human γHV, MHV-68 encodes 15 microRNAs (miRNAs). Although their functions remain unknown, they are thought to regulate the viral life cycle or host-virus interactions, similarly to other human γHV. Herein, we established stable cell lines expressing MHV-68 miRNAs and investigated the role of MHV-68 miRNAs in the regulation of viral life cycle. We found that mghv-miR-M1-1, -3, -5, -7, -8, -9, -10, -11, -13, and -15 repressed MHV-68 lytic replication by down-regulating expression of the replication and transcription activator (RTA) gene, whereas mghv-miR-M1-2, -4, -6, and -12 induced lytic replication by up-regulating RTA. We confirmed that the decrease in viral replication caused by mghv-miR-M1-1 was abolished by inhibition of miRNA expression via miRNA inhibitor treatment. In addition, we observed that mghv-miR-M1-1 down-regulated c-Jun indirectly and decreased cytokine production, suggesting that mghv-miR-M1-1 may inhibit MHV-68 lytic replication by inhibiting the activator protein 1 (AP-1) signaling pathway.

MeSH terms

  • Animals
  • Gene Expression Regulation, Viral*
  • Herpesviridae Infections / veterinary*
  • Herpesviridae Infections / virology
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA, Viral / genetics
  • RNA, Viral / metabolism*
  • Rhadinovirus / genetics
  • Rhadinovirus / growth & development*
  • Rhadinovirus / physiology
  • Rodent Diseases / virology*
  • Rodentia
  • Virus Latency
  • Virus Replication

Substances

  • MicroRNAs
  • RNA, Viral