title: Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations.
abstract: Reversal of HIV-1 latency by small molecules is a potential cure strategy. This approach will likely require effective drug combinations to achieve high levels of latency reversal. Using resting CD4+ T cells (rCD4s) from infected individuals, we developed an experimental and theoretical framework to identify effective latency-reversing agent (LRA) combinations. Utilizing ex vivo assays for intracellular HIV-1 mRNA and virion production, we compared 2-drug combinations of leading candidate LRAs and identified multiple combinations that effectively reverse latency. We showed that protein kinase C agonists in combination with bromodomain inhibitor JQ1 or histone deacetylase inhibitors robustly induce HIV-1 transcription and virus production when directly compared with maximum reactivation by T cell activation. Using the Bliss independence model to quantitate combined drug effects, we demonstrated that these combinations synergize to induce HIV-1 transcription. This robust latency reversal occurred without release of proinflammatory cytokines by rCD4s. To extend the clinical utility of our findings, we applied a mathematical model that estimates in vivo changes in plasma HIV-1 RNA from ex vivo measurements of virus production. Our study reconciles diverse findings from previous studies, establishes a quantitative experimental approach to evaluate combinatorial LRA efficacy, and presents a model to predict in vivo responses to LRAs.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Laird
authors.forename: C Korin
authors.initials: CK
authors.lastname: Bullen
authors.forename: Daniel I S
authors.initials: DI
authors.lastname: Rosenbloom
authors.forename: Alyssa R
authors.initials: AR
authors.lastname: Martin
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hill
authors.forename: Christine M
authors.initials: CM
authors.lastname: Durand
authors.forename: Janet D
authors.initials: JD
authors.lastname: Siliciano
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001381:Azepines / Q000494:pharmacology*; D054713:Bryostatins / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D004221:Disulfiram / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D014771:Virion / Q000378:metabolism; D017735:Virus Latency / Q000187:drug effects*
chemical_list: C561695:(+)-JQ1 compound; D019380:Anti-HIV Agents; D001381:Azepines; D054713:Bryostatins; D056572:Histone Deacetylase Inhibitors; D008222:Lymphokines; D010703:Phorbol Esters; D012333:RNA, Messenger; D012367:RNA, Viral; D014230:Triazoles; C046785:bryostatin 1; C070999:prostratin; D011493:Protein Kinase C; D004221:Disulfiram
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