title: Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy.
abstract: Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
authors: The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors: N M
authors: NM
authors: Archin
authors: A L
authors: AL
authors: Liberty
authors: A D
authors: AD
authors: Kashuba
authors: S K
authors: SK
authors: Choudhary
authors: J D
authors: JD
authors: Kuruc
authors: A M
authors: AM
authors: Crooks
authors: D C
authors: DC
authors: Parker
authors: E M
authors: EM
authors: Anderson
authors: M F
authors: MF
authors: Kearney
authors: M C
authors: MC
authors: Strain
authors: D D
authors: DD
authors: Richman
authors: M G
authors: MG
authors: Hudgens
authors: R J
authors: RJ
authors: Bosch
authors: J M
authors: JM
authors: Coffin
authors: J J
authors: JJ
authors: Eron
authors: D J
authors: DJ
authors: Hazuda
authors: D M
authors: DM
authors: Margolis
mesh_terms: D000107:Acetylation / Q000187:drug effects; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011533:Proviruses / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D012367:RNA, Viral / Q000096:biosynthesis / Q000097:blood; D018570:Risk Assessment; D015854:Up-Regulation / Q000187:drug effects; D014766:Viremia / Q000188:drug therapy / Q000821:virology; D017735:Virus Latency / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D012367:RNA, Viral; D000077337:Vorinostat