title: Proximity to PML nuclear bodies regulates HIV-1 latency in CD4+ T cells.
abstract: Nuclear bodies (NBs), characterized by the presence of the promyelocytic leukemia (PML) protein, are important components of the nuclear architecture, contributing to genetic and epigenetic control of gene expression. In investigating the mechanisms mediating HIV-1 latency, we determined that silenced but transcriptionally competent HIV-1 proviruses reside in close proximity to PML NBs and that this association inhibits HIV-1 gene expression. PML binds to the latent HIV-1 promoter, which coincides with transcriptionally inactive facultative heterochromatic marks, notably H3K9me2, at the viral genome. PML degradation and NB disruption result in strong activation of viral transcription as well as release of G9a, the major methyltransferase responsible for H3K9me2, and loss of facultative heterochromatin marks from the proviral DNA. Additionally, HIV-1 transcriptional activation requires proviral displacement from PML NBs by active nuclear actin polymerization. Thus, nuclear topology and active gene movement mediate HIV-1 transcriptional regulation and have implications for controlling HIV-1 latency and eradication.
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology ICGEB, 34149 Trieste, Italy. lusic@icgeb.org
authors.forename: Marina
authors.initials: M
authors.lastname: Lusic
authors.forename: Bruna
authors.initials: B
authors.lastname: Marini
authors.forename: Hashim
authors.initials: H
authors.lastname: Ali
authors.forename: Bojana
authors.initials: B
authors.lastname: Lucic
authors.forename: Roberto
authors.initials: R
authors.lastname: Luzzati
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D015497:HIV-1 / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D011533:Proviruses / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D017735:Virus Latency
chemical_list: D004279:DNA, Viral; D006657:Histones; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human