title: HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.
abstract: BACKGROUND
  A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.
  
  
  METHODS
  Five participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed.
  
  
  RESULTS
  VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged.
  
  
  CONCLUSIONS
  Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined.
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Archin
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Bateson
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Tripathy
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Crooks
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Noelle P
authors.initials: NP
authors.lastname: Dahl
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Mary F
authors.initials: MF
authors.lastname: Kearney
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Anderson
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland Departments of Genetics and Molecular Biology, Tufts University School of Medicine, School of Public Health, Boston, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Coffin
authors.affiliation: Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System, La Jolla.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Strain
authors.affiliation: Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System, La Jolla.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Robertson
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kashuba
authors.affiliation: Department of Biostatistics, School of Public Health, Boston, Massachusetts.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Bosch
authors.affiliation: Merck Research Laboratories, White Horse Junction, Pennsylvania.
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Joann D
authors.initials: JD
authors.lastname: Kuruc
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill.
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
mesh_terms: D000328:Adult; D001769:Blood / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology*; D004279:DNA, Viral / Q000032:analysis / Q000235:genetics; D015497:HIV-1 / Q000254:growth & development*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D000077337:Vorinostat
chemical_list: D004279:DNA, Viral; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012367:RNA, Viral; D000077337:Vorinostat
keywords: HDAC inhibitor; HIV; acetylation; histone; latency; vorinostat