Epigenetic regulation of HIV-1 latency by cytosine methylation.
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.
Kauder
Steven E
SE
Gladstone Institute of Virology and Immunology, San Francisco, California, United States of America.
Bosque
Alberto
A
Lindqvist
Annica
A
Planelles
Vicente
V
Verdin
Eric
E
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018899:CpG Islands; D003596:Cytosine / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000077209:Decitabine; D044127:Epigenesis, Genetic; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D014162:Transfection; D017735:Virus Latency / Q000235:genetics*
D004268:DNA-Binding Proteins; C489325:MBD2 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077209:Decitabine; D003596:Cytosine; D001374:Azacitidine