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Dual effect of the broad spectrum kinase inhibitor midostaurin in acute and latent HIV-1 infection.
Garcia-Vidal, Edurne; Badia, Roger; Pujantell, Maria; Castellví, Marc; Felip, Eudald; Clotet, Bonaventura; Riveira-Muñoz, Eva; Ballana, Ester; Esté, José A.
Afiliação
  • Garcia-Vidal E; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • Badia R; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • Pujantell M; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • Castellví M; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • Felip E; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • Clotet B; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • Riveira-Muñoz E; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
  • Ballana E; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. Electronic address: eballana@irsicaixa.es.
  • Esté JA; AIDS Research Institute - IrsiCaixa, AIDS Unit and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. Electronic address: jaeste@irsicaixa.es.
Antiviral Res ; 168: 18-27, 2019 08.
Article em En | MEDLINE | ID: mdl-31077767
Midostaurin is a multi-kinase inhibitor with antineoplastic activity. We assessed the capacity of midostaurin to affect early and late steps of HIV-1 infection and to reactivate HIV-1 latently infected cells, alone or in combination with histone deacetylase inhibitors (HDACi) known to act as latency-reversing agents (LRA). Acute HIV-1 infection was assessed by flow cytometry in three cell types treated with midostaurin in the presence or absence of SAMHD1. Non-infected cells were treated with midostaurin and harvested for Western blot analysis. Macrophage infections were also measured by quantitative RT-PCR. HIV-1 latency reactivation was assessed in several latency models. Midostaurin induced G2/M arrest and inhibited CDK2, preventing the phosphorylation of SAMHD1 associated to inhibition of its dNTPase activity. In the presence of SAMHD1, midostaurin blocked HIV-1 DNA formation and viral replication. However, following Vpx-mediated SAMHD1 degradation, midostaurin increased viral transcripts and virus replication. In three out of four HIV-1 latency models, including primary CD4+ T cells, midostaurin effectively reversed HIV-1 latency and was synergistic in combination with LRA vorinostat and panobinostat. Our study describes a dual effect for midostaurin in HIV-1 infection, antiviral or proviral depending on SAMHD1 activation, and highlights a role for active SAMHD1 in regulating the activity of potential HIV-1 latency reversal agents.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por HIV / HIV-1 / Latência Viral / Estaurosporina / Inibidores de Proteínas Quinases Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por HIV / HIV-1 / Latência Viral / Estaurosporina / Inibidores de Proteínas Quinases Idioma: En Ano de publicação: 2019 Tipo de documento: Article