title: New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo.
abstract: HIV-1 persists in a latent reservoir despite antiretroviral therapy (ART). This reservoir is the major barrier to HIV-1 eradication. Current approaches to purging the latent reservoir involve pharmacologic induction of HIV-1 transcription and subsequent killing of infected cells by cytolytic T lymphocytes (CTLs) or viral cytopathic effects. Agents that reverse latency without activating T cells have been identified using in vitro models of latency. However, their effects on latently infected cells from infected individuals remain largely unknown. Using a new ex vivo assay, we demonstrate that none of the latency-reversing agents (LRAs) tested induced outgrowth of HIV-1 from the latent reservoir of patients on ART. Using a quantitative reverse transcription PCR assay specific for all HIV-1 mRNAs, we demonstrate that LRAs that do not cause T cell activation do not induce substantial increases in intracellular HIV-1 mRNA in patient cells; only the protein kinase C agonist bryostatin-1 caused significant increases. These findings demonstrate that current in vitro models do not fully recapitulate mechanisms governing HIV-1 latency in vivo. Further, our data indicate that non-activating LRAs are unlikely to drive the elimination of the latent reservoir in vivo when administered individually.
authors.affiliation: 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2].
authors.forename: C Korin
authors.initials: CK
authors.lastname: Bullen
authors.affiliation: 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2].
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Laird
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Durand
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Siliciano
authors.affiliation: 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Howard Hughes Medical Institute, Baltimore, Maryland, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D054713:Bryostatins / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018797:Cell Cycle Proteins; D047630:Depsipeptides / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D000077767:Panobinostat; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology; D017735:Virus Latency / Q000187:drug effects* / Q000276:immunology; D000077337:Vorinostat; D000092468:Bromodomain Containing Proteins
chemical_list: D019380:Anti-HIV Agents; D001381:Azepines; D054713:Bryostatins; D018797:Cell Cycle Proteins; D047630:Depsipeptides; D004221:Disulfiram; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D015759:Ionomycin; D009687:Nuclear Proteins; D000077767:Panobinostat; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D014230:Triazoles; D000077337:Vorinostat; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C046785:bryostatin 1; C087123:romidepsin