title: Antiretroviral drugs do not interfere with bryostatin-mediated HIV-1 latency reversal.
abstract: Although an effective combination of antiretroviral therapy (cART) controls HIV-1 viraemia in infected patients, viral latency established soon after infection hinders HIV-1 eradication. It has been shown that bryostatin-1 (BRY) inhibits HIV-infection in vitro and reactivates the latent virus through the protein kinase C-NF-κB pathway. We determined the in vitro potential effect of BRY in combination with currently used antiretroviral drugs. BRY alone or in combination with maraviroc (MVC)/Atripla (ATP) was tested for its capacity to reactivate latent virus and inhibit new infections. JLTRG-R5 cells and two latent HIV-1-infected cell lines, J89GFP and THP89GFP, were used as latency models. To quantify HIV infection, the reporter cell line TZM-bl was used. We found that BRY reactivates HIV-1 even in combination with MVC or ATP. Antiretroviral combinations with BRY do not interfere with BRY activity (i.e., the reactivation of latently infected cells) or with the antiviral activity of antiretroviral drugs. In addition, BRY-mediated down-modulation of surface CD4 and CXCR4 was not affected when it was used in combination with other antiretrovirals, and no hyperactivation or high-proliferation effects were observed in primary T cells. Moreover, the BRY treatment was able to reactivate HIV-1 in CD4+ T cells from HIV-1-infected patients under cART. Thus, we propose the use of BRY to purge the viral reservoir and recommend its combination with current antiretroviral treatments.
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain. Electronic address: marta.mtnezb@gmail.com.
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-Bonet
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and 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. Electronic address: maribel.clemente@iisgm.com.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Clemente
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain. Electronic address: salosada@salud.madrid.org.
authors.forename: Susana
authors.initials: S
authors.lastname: Álvarez
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain; Unidad de Citometria y Sorter, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), C/ Dr. Esquerdo 46, 28007 Madrid, Spain. Electronic address: lauradiaz@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Díaz
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain. Electronic address: mdgalonso@gmail.com.
authors.forename: Dolores
authors.initials: D
authors.lastname: García-Alonso
authors.affiliation: Departamento de Inmunología, Facultad de Medicina, Universidad de Córdoba, Avda. Menéndez Pidal, s/n, 14004 Córdoba, Spain. Electronic address: fi1muble@uco.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.affiliation: Servicio de Enfermedades Infecciosas, Hospital Universitario Ramón y Cajal and IRYCIS, Ctra. de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain. Electronic address: smoreno.hrc@salud.madrid.org.
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C/ Dr. Esquerdo 46, 28007 Madrid, Spain. Electronic address: mmunoz.hgugm@gmail.com.
authors.forename: Maria Ángeles
authors.initials: MÁ
authors.lastname: Muñoz-Fernández
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000378:metabolism*; D054713:Bryostatins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000378:metabolism; D004347:Drug Interactions; D000068257:Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D014230:Triazoles / Q000378:metabolism; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D044966:Anti-Retroviral Agents; D054713:Bryostatins; D003510:Cyclohexanes; D000068257:Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D014230:Triazoles; D000077592:Maraviroc
keywords: Atripla; Bryostatin-1; HIV-latency; HIV-reactivation; Maraviroc