title: Selective HDAC inhibition for the disruption of latent HIV-1 infection.
abstract: Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized a combination of small molecule inhibitors and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) to be targeted for selective induction of latent HIV-1 expression. Individual depletion of HDAC3 significantly induced expression from the HIV-1 promoter in the 2D10 latency cell line model. However, depletion of HDAC1 or -2 alone or in combination did not significantly induce HIV-1 expression. Co-depletion of HDAC2 and -3 resulted in a significant increase in expression from the HIV-1 promoter. Furthermore, concurrent knockdown of HDAC1, -2, and -3 resulted in a significant increase in expression from the HIV-1 promoter. Using small molecule HDAC inhibitors of differing selectivity to ablate the residual HDAC activity that remained after (sh)RNA depletion, the effect of depletion of HDAC3 was further enhanced. Enzymatic inhibition of HDAC3 with the selective small-molecule inhibitor BRD3308 activated HIV-1 transcription in the 2D10 cell line. Furthermore, ex vivo exposure to BRD3308 induced outgrowth of HIV-1 from resting CD4+ T cells isolated from antiretroviral-treated, aviremic HIV+ patients. Taken together these findings suggest that HDAC3 is an essential target to disrupt HIV-1 latency, and inhibition of HDAC2 may also contribute to the effort to purge and eradicate latent HIV-1 infection.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kirston M
authors.initials: KM
authors.lastname: Barton
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Nancie M
authors.initials: NM
authors.lastname: Archin
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kara S
authors.initials: KS
authors.lastname: Keedy
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, United States of America.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Yan-ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gale
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000821:virology; D002461:Cell Line, Transformed; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics*; D054884:Host-Pathogen Interactions; D006801:Humans; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017735:Virus Latency; D000099186:Histone Deacetylase 3
chemical_list: D019380:Anti-HIV Agents; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D034741:RNA, Small Interfering; D000099186:Histone Deacetylase 3; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human