title: Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells.
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.
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
authors: Mercedes
authors: M
authors: Bermejo
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
authors: María Rosa
authors: MR
authors: López-Huertas
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
authors: Javier
authors: J
authors: García-Pérez
authors: Retrovirology and Viral Immunopathology Laboratory, AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors: Núria
authors: N
authors: Climent
authors: Laboratory of Molecular Virology, Institute of Human Genetics, Montpellier, France.
authors: Benjamin
authors: B
authors: Descours
authors: Infectious Diseases Service, AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors: Juan
authors: J
authors: Ambrosioni
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
authors: Elena
authors: E
authors: Mateos
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
authors: Sara
authors: S
authors: Rodríguez-Mora
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
authors: Lucía
authors: L
authors: Rus-Bercial
authors: Laboratory of Molecular Virology, Institute of Human Genetics, Montpellier, France.
authors: Monsef
authors: M
authors: Benkirane
authors: Infectious Diseases Service, AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors: José M
authors: JM
authors: Miró
authors: Retrovirology and Viral Immunopathology Laboratory, AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors: Montserrat
authors: M
authors: Plana
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
authors: José
authors: J
authors: Alcamí
authors: AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: mcoiras@isciii.es.
authors: Mayte
authors: M
authors: Coiras
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D054884:Host-Pathogen Interactions; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015398:Signal Transduction; D018116:Vesiculovirus / Q000235:genetics; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014760:Viral Fusion Proteins; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins; D000069439:Dasatinib
keywords: CD4+ T lymphocytes; Chronic myeloid leukemia; Dasatinib; HIV-1 reservoir; SAMHD1