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dc.contributor.author | Bermejo, Mercedes | |
dc.contributor.author | Lopez-Huertas, Maria Rosa | |
dc.contributor.author | García-Pérez, Javier | |
dc.contributor.author | Climent, Núria | |
dc.contributor.author | Descours, Benjamin | |
dc.contributor.author | Ambrosioni, Juan | |
dc.contributor.author | Mateos, Elena | |
dc.contributor.author | Rodriguez‑Mora, Sara | |
dc.contributor.author | Rus-Bercial, Lucía | |
dc.contributor.author | Benkirane, Monsef | |
dc.contributor.author | Miró, José M | |
dc.contributor.author | Plana, Montserrat | |
dc.contributor.author | Alcamí, José | |
dc.contributor.author | Coiras, Mayte | |
dc.date.accessioned | 2020-06-09T10:47:08Z | |
dc.date.available | 2020-06-09T10:47:08Z | |
dc.date.issued | 2016-04-15 | |
dc.identifier.citation | Biochem Pharmacol. 2016 Apr 15;106:30-45. d | es_ES |
dc.identifier.issn | 0006-2952 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/10303 | |
dc.description.abstract | Massive activation of infected CD4+ T cells during acute HIV-1 infection leads to reservoir seeding and T-cell destruction. During T-cell activation, the antiviral effect of the innate factor SAMHD1 is neutralized through phosphorylation at T592, allowing HIV-1 infection. Dasatinib, a tyrosine kinase inhibitor currently used for treating chronic myeloid leukemia, has been described to control HIV-1 replication through its negative effect on T-cell proliferation and viral entry. We demonstrate that Dasatinib can actually interfere with SAMHD1 phosphorylation in human peripheral blood lymphocytes, preserving its antiviral activity against HIV-1. Dasatinib prevented SAMHD1 phosphorylation in vitro and ex vivo, impairing HIV-1 reverse transcription and proviral integration. This was the major mechanism of action because the presence of Vpx, which degrades SAMHD1, in HIV-1 virions impeded the inhibitory effect of Dasatinib on HIV-1 replication. In fact, infection with VSV-pseudotyped HIV-1 virions and fusion of BlaM-Vpr-containing HIV-1 viruses with activated PBMCs in the presence of Dasatinib suggested that Dasatinib was not acting at fusion level. Finally, PBMCs from patients on chronic treatment with Dasatinib showed a lower level of SAMHD1 phosphorylation in response to activating stimuli and low susceptibility to HIV-1 infection ex vivo. Consequently, Dasatinib is a compound currently used in clinic that preserves the antiviral function of SAMHD1. Using Dasatinib as adjuvant of antiretroviral therapy during early primary HIV-1 infection would contribute to reduce viral replication and spread, prevent reservoir seeding, and preserve CD4 counts and CTL responses. These events would create a more favorable virologic and immunologic environment for future interventional studies aiming at HIV-1 eradication. | es_ES |
dc.description.sponsorship | This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2010-18388, SAF2013-44677-R, FIS PI12/00506, and FIS PI12/00969); the SPANISH AIDS Research Network RD12/0017/0015 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011, Instituto de Salud Carlos III, European Region Development Fund (ERDF); Bristol-Myers Squibb (BMS AI471-041); AIM-HIV Network of Excellence of the EU, grant number HEALTH-F3-2012-305938; joined program of the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS AO2014-2); and the European FP7-HEALTH project HIT HIDDEN HIV. The work of Elena Mateos is supported by the Instituto de Salud Carlos III (Spain) (MPY 1371/12). The work of Sara Rodríguez-Mora is supported by a fellowship of Sara Borrell from Spanish Ministry of Economy and Competitiveness. The work of María Rosa López-Huertas is supported by a fellowship of the European Union Programme Health 2009 (CHAARM). The work of Dr Benjamin Descours is supported by the 31 European FP7-HEALTH project HIT HIDDEN HIV. Dr. Montserrat Plana is a researcher at the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and is supported by the Spanish Health Institute Carlos III (ISCIII) and the Health Department of the Catalan Government (Generalitat de Catalunya). Dr. Juan Ambrosioni developed this work in the framework of a ‘Juan de la Cierva 2012’ post- doctoral program, Ministerio de Competitividad, Madrid, Spain. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.type.hasVersion | AM | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject | CD4+ T lymphocytes | es_ES |
dc.subject | Chronic myeloid leukemia | es_ES |
dc.subject | Dasatinib | es_ES |
dc.subject | HIV-1 reservoir | es_ES |
dc.subject | SAMHD1 | es_ES |
dc.subject.mesh | Adult | es_ES |
dc.subject.mesh | Anti-HIV Agents | es_ES |
dc.subject.mesh | Antineoplastic Agents | es_ES |
dc.subject.mesh | CD4-Positive T-Lymphocytes | es_ES |
dc.subject.mesh | Cell Proliferation | es_ES |
dc.subject.mesh | Dasatinib | es_ES |
dc.subject.mesh | Female | es_ES |
dc.subject.mesh | Gene Expression Regulation | es_ES |
dc.subject.mesh | HIV Infections | es_ES |
dc.subject.mesh | HIV-1 | es_ES |
dc.subject.mesh | Host-Pathogen Interactions | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Leukemia, Myelogenous, Chronic, BCR-ABL Positive | es_ES |
dc.subject.mesh | Lymphocyte Activation | es_ES |
dc.subject.mesh | Male | es_ES |
dc.subject.mesh | Monomeric GTP-Binding Proteins | es_ES |
dc.subject.mesh | Phosphorylation | es_ES |
dc.subject.mesh | Protein Kinase Inhibitors | es_ES |
dc.subject.mesh | SAM Domain and HD Domain-Containing Protein 1 | es_ES |
dc.subject.mesh | Signal Transduction | es_ES |
dc.subject.mesh | Vesiculovirus | es_ES |
dc.subject.mesh | Viral Fusion Proteins | es_ES |
dc.subject.mesh | Virus Internalization | es_ES |
dc.subject.mesh | Virus Replication | es_ES |
dc.title | Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.pubmedID | 26851491 | es_ES |
dc.format.volume | 106 | es_ES |
dc.format.page | 30-45 | es_ES |
dc.identifier.doi | 10.1016/j.bcp.2016.02.002 | es_ES |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | |
dc.contributor.funder | Red de Investigación Cooperativa en Investigación en Sida (España) | |
dc.contributor.funder | Instituto de Salud Carlos III | |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | |
dc.contributor.funder | Unión Europea. Comisión Europea. 7 Programa Marco | |
dc.contributor.funder | Government of Catalonia (España) | |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1873-2968 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1016/j.bcp.2016.02.002 | es_ES |
dc.identifier.journal | Biochemical pharmacology | es_ES |
dc.repisalud.centro | ISCIII::Centro Nacional de Microbiología | es_ES |
dc.repisalud.institucion | ISCIII | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SAF2010-18388 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SAF2013-44677-R | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/FIS PI12/00506 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/FIS PI12/00969 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/RD12/0017/0015 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/BMS AI471-041 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/HEALTH-F3-2012-305938 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/ANRS AO2014-2 | |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/MPY 1371/12 | |
dc.rights.accessRights | open access | es_ES |