title: Reactivation of Latent HIV-1 Expression by Engineered TALE Transcription Factors.
abstract: The presence of replication-competent HIV-1 -which resides mainly in resting CD4+ T cells--is a major hurdle to its eradication. While pharmacological approaches have been useful for inducing the expression of this latent population of virus, they have been unable to purge HIV-1 from all its reservoirs. Additionally, many of these strategies have been associated with adverse effects, underscoring the need for alternative approaches capable of reactivating viral expression. Here we show that engineered transcriptional modulators based on customizable transcription activator-like effector (TALE) proteins can induce gene expression from the HIV-1 long terminal repeat promoter, and that combinations of TALE transcription factors can synergistically reactivate latent viral expression in cell line models of HIV-1 latency. We further show that complementing TALE transcription factors with Vorinostat, a histone deacetylase inhibitor, enhances HIV-1 expression in latency models. Collectively, these findings demonstrate that TALE transcription factors are a potentially effective alternative to current pharmacological routes for reactivating latent virus and that combining synthetic transcriptional activators with histone deacetylase inhibitors could lead to the development of improved therapies for latent HIV-1 infection.
authors.affiliation: Research Institute for Medicines (iMed ULisboa), Faculdadede Farmácia, Universidade de Lisboa, Lisboa, Portugal.|The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.|Departments of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Pedro
authors.initials: P
authors.lastname: Perdigão
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.|Departments of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gaj
authors.affiliation: Research Institute for Medicines (iMed ULisboa), Faculdadede Farmácia, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Santa-Marta
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.|Departments of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America.|Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Barbas
authors.affiliation: Research Institute for Medicines (iMed ULisboa), Faculdadede Farmácia, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Joao
authors.initials: J
authors.lastname: Goncalves
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D017735:Virus Latency / Q000187:drug effects / Q000235:genetics*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics*; D000077337:Vorinostat
chemical_list: D051696:Activating Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat