title: CpG methylation controls reactivation of HIV from latency.
abstract: DNA methylation of retroviral promoters and enhancers localized in the provirus 5' long terminal repeat (LTR) is considered to be a mechanism of transcriptional suppression that allows retroviruses to evade host immune responses and antiretroviral drugs. However, the role of DNA methylation in the control of HIV-1 latency has never been unambiguously demonstrated, in contrast to the apparent importance of transcriptional interference and chromatin structure, and has never been studied in HIV-1-infected patients. Here, we show in an in vitro model of reactivable latency and in a latent reservoir of HIV-1-infected patients that CpG methylation of the HIV-1 5' LTR is an additional epigenetic restriction mechanism, which controls resistance of latent HIV-1 to reactivation signals and thus determines the stability of the HIV-1 latency. CpG methylation acts as a late event during establishment of HIV-1 latency and is not required for the initial provirus silencing. Indeed, the latent reservoir of some aviremic patients contained high proportions of the non-methylated 5' LTR. The latency controlled solely by transcriptional interference and by chromatin-dependent mechanisms in the absence of significant promoter DNA methylation tends to be leaky and easily reactivable. In the latent reservoir of HIV-1-infected individuals without detectable plasma viremia, we found HIV-1 promoters and enhancers to be hypermethylated and resistant to reactivation, as opposed to the hypomethylated 5' LTR in viremic patients. However, even dense methylation of the HIV-1 5'LTR did not confer complete resistance to reactivation of latent HIV-1 with some histone deacetylase inhibitors, protein kinase C agonists, TNF-alpha, and their combinations with 5-aza-2deoxycytidine: the densely methylated HIV-1 promoter was most efficiently reactivated in virtual absence of T cell activation by suberoylanilide hydroxamic acid. Tight but incomplete control of HIV-1 latency by CpG methylation might have important implications for strategies aimed at eradicating HIV-1 infection.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMR891, Centre de Recherche en Cancérologie de Marseille; and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Jana
authors.initials: J
authors.lastname: Blazkova
authors.forename: Katerina
authors.initials: K
authors.lastname: Trejbalova
authors.forename: Françoise
authors.initials: F
authors.lastname: Gondois-Rey
authors.forename: Philippe
authors.initials: P
authors.lastname: Halfon
authors.forename: Patrick
authors.initials: P
authors.lastname: Philibert
authors.forename: Allan
authors.initials: A
authors.lastname: Guiguen
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Jiri
authors.initials: J
authors.lastname: Hejnar
authors.forename: Ivan
authors.initials: I
authors.lastname: Hirsch
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002843:Chromatin / Q000502:physiology; D002999:Clone Cells; D003001:Cloning, Molecular; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015658:HIV Infections / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D018023:HIV Seronegativity; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011533:Proviruses / Q000235:genetics / Q000378:metabolism; D014766:Viremia / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency / Q000502:physiology*
chemical_list: D002843:Chromatin
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