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PLoS Pathog. 2009 Jun;5(6):e1000495. doi: 10.1371/journal.ppat.1000495. Epub 2009 Jun 26.

Epigenetic regulation of HIV-1 latency by cytosine methylation.

Author information

1
Gladstone Institute of Virology and Immunology, San Francisco, California, United States of America.

Abstract

Human immunodeficiency virus type 1 (HIV-1) persists in a latent state within resting CD4+ T cells of infected persons treated with highly active antiretroviral therapy (HAART). This reservoir must be eliminated for the clearance of infection. Using a cDNA library screen, we have identified methyl-CpG binding domain protein 2 (MBD2) as a regulator of HIV-1 latency. Two CpG islands flank the HIV-1 transcription start site and are methylated in latently infected Jurkat cells and primary CD4+ T cells. MBD2 and histone deacetylase 2 (HDAC2) are found at one of these CpG islands during latency. Inhibition of cytosine methylation with 5-aza-2'deoxycytidine (aza-CdR) abrogates recruitment of MBD2 and HDAC2. Furthermore, aza-CdR potently synergizes with the NF-kappaB activators prostratin or TNF-alpha to reactivate latent HIV-1. These observations confirm that cytosine methylation and MBD2 are epigenetic regulators of HIV-1 latency. Clearance of HIV-1 from infected persons may be enhanced by inclusion of DNA methylation inhibitors, such as aza-CdR, and NF-kappaB activators into current antiviral therapies.

PMID:
19557157
PMCID:
PMC2695767
DOI:
10.1371/journal.ppat.1000495
[Indexed for MEDLINE]
Free PMC Article

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