A virus-induced circular RNA maintains latent infection of Kaposi's sarcoma herpesvirus

Proc Natl Acad Sci U S A. 2023 Feb 7;120(6):e2212864120. doi: 10.1073/pnas.2212864120. Epub 2023 Feb 1.


Non-coding RNAs (ncRNAs) play important roles in host-pathogen interactions; oncogenic viruses like Kaposi's sarcoma herpesvirus (KSHV) employ ncRNAs to establish a latent reservoir and persist for the life of the host. We previously reported that KSHV infection alters a novel class of RNA, circular RNAs (circRNAs). CircRNAs are alternative splicing isoforms and regulate gene expression, but their importance in infection is largely unknown. Here, we showed that a human circRNA, hsa_circ_0001400, is induced by various pathogenic viruses, namely KSHV, Epstein-Barr virus, and human cytomegalovirus. The induction of circRNAs including circ_0001400 by KSHV is co-transcriptionally regulated, likely at splicing. Consistently, screening for circ_0001400-interacting proteins identified a splicing factor, PNISR. Functional studies using infected primary endothelial cells revealed that circ_0001400 inhibits KSHV lytic transcription and virus production. Simultaneously, the circRNA promoted cell cycle, inhibited apoptosis, and induced immune genes. RNA-pull down assays identified transcripts interacting with circ_0001400, including TTI1, which is a component of the pro-growth mTOR complexes. We thus identified a circRNA that is pro-growth and anti-lytic replication. These results support a model in which KSHV induces circ_0001400 expression to maintain latency. Since circ_0001400 is induced by multiple viruses, this novel viral strategy may be widely employed by other viruses.

Keywords: HHV8; KSHV; circular RNAs; herpesvirus.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endothelial Cells
  • Epstein-Barr Virus Infections*
  • Gene Expression Regulation, Viral
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 8, Human* / genetics
  • Humans
  • Latent Infection*
  • RNA Viruses* / genetics
  • RNA, Circular / genetics
  • RNA, Untranslated
  • RNA, Viral / genetics
  • Sarcoma, Kaposi* / genetics
  • Virus Latency / genetics
  • Virus Replication / genetics


  • RNA, Circular
  • RNA, Viral
  • RNA, Untranslated