The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response.
Latent HIV-1 (human immunodeficiency virus-1) provirus is unaffected by current AIDS (acquired immunodeficiency syndrome) therapies. We show here that chaetocin, an SUV39H1 histone methyltransferase inhibitor, causes 25-fold induction of latent HIV-1 expression, while producing minimal toxicity and without causing T cell activation. Induction is associated with loss of histone H3 lysine 9 (H3K9) trimethylation at the long terminal repeat (LTR) promoter, and a corresponding increase in H3K9 acetylation. The effect of chaetocin is amplified synergistically in combination with histone deacetylase (HDAC) inhibitors. These results indicate that chaetocin may provide a therapy to purge cells of latent HIV-1, possibly in combination with other chromatin remodeling drugs.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada.
Wendy
W
Bernhard
Kris
K
Barreto
Amy
A
Saunders
Matthew S
MS
Dahabieh
Pauline
P
Johnson
Ivan
I
Sadowski
D000107:Acetylation; D042002:Chromatin Assembly and Disassembly; D004357:Drug Synergism; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency / Q000187:drug effects
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010879:Piperazines; D012097:Repressor Proteins; C002511:chaetocin; C407843:SUV39H1 protein, human; D008780:Methyltransferases