Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/10303
Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells
Bermejo, Mercedes ISCIII | Lopez-Huertas, Maria Rosa ISCIII | Garcia-Perez, Javier ISCIII | Climent, Núria | Descours, Benjamin | Ambrosioni, Juan | Mateos, Elena ISCIII | Rodriguez‑Mora, Sara ISCIII | Rus-Bercial, Lucía | Benkirane, Monsef | Miró, José M | Plana, Montserrat | Alcamí, José ISCIII | Coiras, Mayte ISCIII
Biochem Pharmacol. 2016 Apr 15;106:30-45. d
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.
Adult | Anti-HIV Agents | Antineoplastic Agents | CD4-Positive T-Lymphocytes | Cell Proliferation | Dasatinib | Female | Gene Expression Regulation | HIV Infections | HIV-1 | Host-Pathogen Interactions | Humans | Leukemia, Myelogenous, Chronic, BCR-ABL Positive | Lymphocyte Activation | Male | Monomeric GTP-Binding Proteins | Phosphorylation | Protein Kinase Inhibitors | SAM Domain and HD Domain-Containing Protein 1 | Signal Transduction | Vesiculovirus | Viral Fusion Proteins | Virus Internalization | Virus Replication
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