title: Synergistic Activation of Latent HIV-1 Expression by Novel Histone Deacetylase Inhibitors and Bryostatin-1.
abstract: Viral reactivation from latently infected cells has become a promising therapeutic approach to eradicate HIV. Due to the complexity of the viral latency, combinations of efficient and available drugs targeting different pathways of latency are needed. In this work, we evaluated the effect of various combinations of bryostatin-1 (BRY) and novel histone deacetylase inhibitors (HDACIs) on HIV-reactivation and on cellular phenotype. The lymphocyte (J89GFP) or monocyte/macrophage (THP89GFP) latently infected cell lines were treated with BRY, panobinostat (PNB) and romidepsin (RMD) either alone or in combination. Thus, the effect on the viral reactivation was evaluated. We calculated the combination index for each drug combination; the BRY/HDACIs showed a synergistic HIV-reactivation profile in the majority of the combinations tested, whereas non-synergistic effects were observed when PNB was mixed with RMD. Indeed, the 75% effective concentrations of BRY, PNB and RMD were reduced in these combinations. Moreover, primary CD4 T cells treated with such drug combinations presented similar activation and proliferation profiles in comparison with single drug treated cells. Summing up, combinations between BRY, PNB and/or RMD presented a synergistic profile by inducing virus expression in HIV-latently infected cells, rendering these combinations an attractive novel and safe option for future clinical trials.
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón; Spanish HIV BioBank, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), C/Dr. Esquerdo 46, 28007 Madrid, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN); C/Dr. Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-Bonet
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón; Spanish HIV BioBank, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), C/Dr. Esquerdo 46, 28007 Madrid, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN); C/Dr. Esquerdo 46, 28007 Madrid, Spain.|Unidad de cultivos celulares, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), C/Dr. Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Clemente
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón; Spanish HIV BioBank, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), C/Dr. Esquerdo 46, 28007 Madrid, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN); C/Dr. Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Serramía
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigaciones Biomédicas de Córdoba (IMIBIC)/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.affiliation: Servicio de Enfermedades Infecciosas, Hospital Universitario Ramón y Cajal and IRYCIS, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón; Spanish HIV BioBank, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), C/Dr. Esquerdo 46, 28007 Madrid, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN); C/Dr. Esquerdo 46, 28007 Madrid, Spain.
authors.forename: Maria Ángeles
authors.initials: MÁ
authors.lastname: Muñoz-Fernández
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D054713:Bryostatins / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D009000:Monocytes / Q000187:drug effects / Q000821:virology; D000077767:Panobinostat; D013997:Time Factors; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D054713:Bryostatins; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; C087123:romidepsin