期刊
PLOS PATHOGENS
卷 5, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1000554
关键词
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资金
- French National Agency for AIDS Research and Viral Hepatitis (ANRS)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Czech Science Foundation [204/05/0939, 204/08/P616]
- Sidaction and Institut Paoli Calmettes
- Plateform Cancer Immuno-Monitoring IBiSA
- Sidaction
- Centre National des Oeuvres Universitaires et Scolaires (CNOUS)
- Fonds Nationales de la Recherche Scientifique (FNRS)
- Academy of Sciences of the Czech Republic [AV0Z50520514]
- Belgian Fund for Scientific Research
- FRS-FNRS
- Action de Recherche Concertee du Ministere de la Communaute Francaise [04/09-309]
- Region Wallonne and the Internationale Brachet Stiftung
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.
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