Epigenetic Regulation of HIV-1 Latency by Cytosine Methylation

PLoS Pathogens

Vicente Planelles¹  Alberto Bosque²  Eric Verdin³  Annica Lindqvist³  Steven E. Kauder⁴ 

[1] Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;Department of Medicine, University of California, San Francisco, California, United States of America;Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America;Gladstone Institute of Virology and Immunology, San Francisco, California, United States of America

关键词: DNA methylation;    HIV-1;    T cells;    Cytosine;    DNA transcription;    Viral replication;    Polymerase chain reaction;    Transcription factors;   

DOI  :  10.1371/journal.ppat.1000495

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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-κB activators prostratin or TNF-α 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-κB activators into current antiviral therapies.

【 授权许可】

CC BY