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Analysis of protein kinase C theta inhibitors for the control of HIV-1 replication in human CD4+ T cells reveals an effect on retrotranscription in addition to viral transcription

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dc.contributor.authorBermejo, Mercedes
dc.contributor.authorLopez-Huertas, Maria Rosa
dc.contributor.authorHedgpeth, Joe
dc.contributor.authorMateos, Elena
dc.contributor.authorRodriguez‑Mora, Sara
dc.contributor.authorMaleno, María José
dc.contributor.authorPlana, Montserrat
dc.contributor.authorSwindle, John
dc.contributor.authorAlcamí, José
dc.contributor.authorCoiras, Mayte
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderRed de Investigación Cooperativa en Investigación en Sida (España)
dc.contributor.funderInstituto de Salud Carlos III
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
dc.contributor.funderAgence Nationale de Recherches sur le sida et les hépatites virales (Francia)
dc.contributor.funderGovernment of Catalonia (España)
dc.date.accessioned2020-06-09T09:54:46Z
dc.date.available2020-06-09T09:54:46Z
dc.date.issued2015-04-15
dc.description.abstractHIV-1 infection cannot be cured due to reservoirs formed early after infection. Decreasing the massive CD4+ T cell activation that occurs at the beginning of the disease would delay reservoir seeding, providing a better prognosis for patients. CD4+ T cell activation is mediated by protein kinase C (PKC) theta (θ), which is involved in T-cell proliferation, as well as NF-κB, NF-AT, and AP-1 activation. We found that PKCθ activity increased viral replication, but also that HIV-1 induced higher activation of PKCθ in infected CD4+ T cells, creating a feedback loop. Therefore, specific inhibition of PKCθ activity could contribute to control HIV-1 replication. We tested the efficacy of seven PKCθ specific inhibitors to control HIV-1 replication in CD4+ T cells and selected two of the more potent and safer: CGX1079 and CGX0471. They reduced PKCθ phosphorylation at T538 and its translocation to the plasma membrane, which correlated with decreased HIV-1 retrotranscription through partial inhibition of SAMHD1 antiviral activity, rendering lower proviral integration. CGX1079 and CGX0471 also interfered with viral transcription, which would reduce the production of new virions, as well as the subsequent spread and infection of new targets that would increase the reservoir size. CGX1079 and CGX0471 did not completely abrogate T-cell functions such as proliferation and CD8-mediated release of IFN-γ in PBMCs from HIV-infected patients, thereby avoiding general immunosuppresion. Consequently, using PKCθ inhibitors as adjuvant of antiretroviral therapy in recently infected patients would decrease the pool of activated CD4+ T cells, thwarting proviral integration and reducing the reservoir size.es_ES
dc.description.peerreviewedSíes_ES
dc.description.sponsorshipWe greatly appreciate the secretarial assistance of Mrs. Olga Palao. We thank Dr. Monsef Benkirane and Dr. Benjamin Descours who kindly provided the specific antibody against SAMHD1 phosphorylated at T592. We also thank Dr. Javier Martı´nez-Picado and Dr. Maria Carmen Puertas (IrsiCaixa Institute for AIDS Research, Badalona, Spain) for their help with the standardization of qPCRs in our laboratory. This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2010-18388, SAF2013-44677-R, FIS PI12/00506, and FIS PI12/00969); FIPSE (360924/10); the SPANISH AIDS Research Network RD12/0017/ 0015 that is included in the Spanish I + D + I Plan and is co-financed by ISCIII-Subdirección General de Evaluacion and European Funding for Regional Development (FEDER); EUROPRISE Network of Excellence of the EU, grant number LSHP CT-2006-037611, and Agence nationale de recherches sur le sida et les he´ patites virales (ANRS 2014-2). The work of Elena Mateos is supported by a contract of the Instituto de Salud Carlos III (Spain) (MPY 1371/12). The work of Sara Rodrı´guez-Mora is supported by a fellowship of Sara Borrell from Spanish Ministry of Economy and Competitiveness. The work of Marı´a Rosa Lo´ pez-Huertas is supported by a fellowship of the European Union Program Health 2009 (CHAARM). Dr. Montserrat Plana is a researcher at the Institut d’Investigacions Biome`diques 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).es_ES
dc.format.number4es_ES
dc.format.page241-56es_ES
dc.format.volume94es_ES
dc.identifier.citationBiochem Pharmacol. 2015 Apr 15;94(4):241-56.es_ES
dc.identifier.doi10.1016/j.bcp.2015.02.009es_ES
dc.identifier.e-issn1873-2968es_ES
dc.identifier.issn0006-2952es_ES
dc.identifier.journalBiochemical pharmacologyes_ES
dc.identifier.pubmedID25732195es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/10298
dc.language.isoenges_ES
dc.publisherElsevieres_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2010-18388es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/SAF2013-44677-Res_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/FIS PI12/00506es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/FIS PI12/00969es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/FIPSE (360924/10es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/RD12/0017/ 0015es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/LSHP CT-2006-037611es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/ANRS 2014-2es_ES
dc.relation.projectIDinfo:eu_repo/grantAgreement/ES/MPY 1371/12es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.bcp.2015.02.009es_ES
dc.repisalud.centroISCIII::Centro Nacional de Microbiologíaes_ES
dc.repisalud.institucionISCIIIes_ES
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAntiretroviral therapyes_ES
dc.subjectHIV-1es_ES
dc.subjectLatent reservoires_ES
dc.subjectProtein kinase C thetaes_ES
dc.subjectSAMHD1es_ES
dc.subject.meshAnti-HIV Agentses_ES
dc.subject.meshCD4-Positive T-Lymphocyteses_ES
dc.subject.meshCell Membranees_ES
dc.subject.meshCell Proliferationes_ES
dc.subject.meshCell Survivales_ES
dc.subject.meshHIV-1es_ES
dc.subject.meshHumanses_ES
dc.subject.meshIsoenzymeses_ES
dc.subject.meshJurkat Cellses_ES
dc.subject.meshMonomeric GTP-Binding Proteinses_ES
dc.subject.meshPhosphorylationes_ES
dc.subject.meshProtein Kinase Ces_ES
dc.subject.meshProtein Kinase C-thetaes_ES
dc.subject.meshProtein Transportes_ES
dc.titleAnalysis of protein kinase C theta inhibitors for the control of HIV-1 replication in human CD4+ T cells reveals an effect on retrotranscription in addition to viral transcriptiones_ES
dc.typejournal articlees_ES
dc.type.hasVersionAMes_ES
dspace.entity.typePublication
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