title: The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion.
abstract: BACKGROUND
  The promyelocytic leukemia (PML) protein, a type I interferon (IFN-I)-induced gene product and a member of the tripartite motif (TRIM) family, modulates the transcriptional activity of viruses belonging to various families. Whether PML has an impact on the replication of HIV-1 has not been fully addressed, but recent studies point to its possible involvement in the restriction of HIV-1 in human cells and in the maintenance of transcriptional latency in human cell lines in which HIV-1 is constitutively repressed. We investigated further the restriction of HIV-1 and a related lentivirus, SIVmac, by PML in murine cells and in a lymphocytic human cell line. In particular, we studied the relevance of PML to IFN-I-mediated inhibition and the role of individual human isoforms.
  
  
  RESULTS
  We demonstrate that both human PML (hPML) and murine PML (mPML) inhibit the early post-entry stages of the replication of HIV-1 and a related lentivirus, SIVmac. In addition, HIV-1 was transcriptionally silenced by mPML and by hPML isoforms I, II, IV and VI in MEFs. This PML-mediated transcriptional repression was attenuated in presence of the histone deacetylase inhibitor SAHA. In contrast, depletion of PML had no effect on HIV-1 gene expression in a human T cell line. PML was found to contribute to the inhibition of HIV-1 by IFN-I. Specifically, IFN-α and IFN-β treatments of MEFs enhanced the PML-dependent inhibition of HIV-1 early replication stages.
  
  
  CONCLUSIONS
  We show that PML can inhibit HIV-1 and other lentiviruses as part of the IFN-I-mediated response. The restriction takes place at two distinct steps, i.e. reverse transcription and transcription, and in an isoform-specific, cellular context-specific fashion. Our results support a model in which PML activates innate immune antilentiviral effectors. These data are relevant to the development of latency reversal-inducing pharmacological agents, since PML was previously proposed as a pharmacological target for such inhibitors. This study also has implications for the development of murine models of HIV-1.
authors.affiliation: Laboratory of Retrovirology, Department of Medical Biology and BioMed Research Group, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada.
authors.forename: Nasser
authors.initials: N
authors.lastname: Masroori
authors.affiliation: Laboratory of Retrovirology, Department of Medical Biology and BioMed Research Group, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada.
authors.forename: Natacha
authors.initials: N
authors.lastname: Merindol
authors.affiliation: Laboratory of Retrovirology, Department of Medical Biology and BioMed Research Group, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada. berthoux@uqtr.ca.
authors.forename: Lionel
authors.identifier: http://orcid.org/0000-0002-7776-5058
authors.initials: L
authors.lastname: Berthoux
mesh_terms: D000818:Animals; D002460:Cell Line; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D048348:Reverse Transcription; D017422:Sequence Analysis, DNA; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human
keywords: HIV-1; Innate immunity; Interferon; Latency; Lentivirus; PML; Restriction factor