title: Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-κB pathway.
abstract: Integration of HIV-1 linear DNA into host chromatin is required for high levels of viral expression, and constitutes a key therapeutic target. Unintegrated viral DNA (uDNA) can support only limited transcription but may contribute to viral propagation, persistence and/or treatment escape under specific situations. The molecular mechanisms involved in the differential expression of HIV uDNA vs integrated genome (iDNA) remain to be elucidated. Here, we demonstrate, for the first time, that the expression of HIV uDNA is mainly supported by 1-LTR circles, and regulated in the opposite way, relatively to iDNA, following NF-κB pathway modulation. Upon treatment activating the NF-κB pathway, NF-κB p65 and AP-1 (cFos/cJun) binding to HIV LTR iDNA correlates with increased iDNA expression, while uDNA expression decreases. On the contrary, inhibition of the NF-κB pathway promotes the expression of circular uDNA, and correlates with Bcl-3 and AP-1 binding to its LTR region. Finally, this study identifies NF-κB subunits and Bcl-3 as transcription factors binding the HIV promoter differently depending on viral genome topology, and opens new insights on the potential roles of episomal genomes during the HIV-1 latency and persistence.
authors.affiliation: LBPA, ENS Cachan, CNRS UMR8113, IDA FR3242, Université Paris-Saclay, F-94235 Cachan, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Thierry
authors.affiliation: LBPA, ENS Cachan, CNRS UMR8113, IDA FR3242, Université Paris-Saclay, F-94235 Cachan, France.
authors.forename: Eloïse
authors.initials: E
authors.lastname: Thierry
authors.affiliation: LBPA, ENS Cachan, CNRS UMR8113, IDA FR3242, Université Paris-Saclay, F-94235 Cachan, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Subra
authors.affiliation: LBPA, ENS Cachan, CNRS UMR8113, IDA FR3242, Université Paris-Saclay, F-94235 Cachan, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deprez
authors.affiliation: LBPA, ENS Cachan, CNRS UMR8113, IDA FR3242, Université Paris-Saclay, F-94235 Cachan, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Leh
authors.affiliation: LBPA, ENS Cachan, CNRS UMR8113, IDA FR3242, Université Paris-Saclay, F-94235 Cachan, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bury-Moné
authors.affiliation: LBPA, ENS Cachan, CNRS UMR8113, IDA FR3242, Université Paris-Saclay, F-94235 Cachan, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delelis
mesh_terms: D002460:Cell Line; D004270:DNA, Circular / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009696:Nucleic Acids / Q000378:metabolism; D011485:Protein Binding; D012367:RNA, Viral / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D016662:Virus Integration / Q000235:genetics*
chemical_list: D004270:DNA, Circular; D004279:DNA, Viral; D016328:NF-kappa B; D009696:Nucleic Acids; D012367:RNA, Viral; D014157:Transcription Factors