2024-03-28T18:43:23Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/103032023-10-05T13:30:05Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2060com_20.500.12105_2052col_20.500.12105_16961col_20.500.12105_2061
Repisalud
author
Bermejo, Mercedes
author
Lopez-Huertas, Maria Rosa
author
García-Pérez, Javier
author
Climent, Núria
author
Descours, Benjamin
author
Ambrosioni, Juan
author
Mateos, Elena
author
Rodriguez‑Mora, Sara
author
Rus-Bercial, Lucía
author
Benkirane, Monsef
author
Miró, José M
author
Plana, Montserrat
author
Alcamí, José
author
Coiras, Mayte
funder
Ministerio de Economía y Competitividad (España)
funder
Red de Investigación Cooperativa en Investigación en Sida (España)
funder
Instituto de Salud Carlos III
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Unión Europea. Comisión Europea. 7 Programa Marco
funder
Government of Catalonia (España)
2020-06-09T10:47:08Z
2020-06-09T10:47:08Z
2016-04-15
Biochem Pharmacol. 2016 Apr 15;106:30-45. d
0006-2952
http://hdl.handle.net/20.500.12105/10303
26851491
10.1016/j.bcp.2016.02.002
1873-2968
Biochemical pharmacology
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.
eng
CD4+ T lymphocytes
Chronic myeloid leukemia
Dasatinib
HIV-1 reservoir
SAMHD1
Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/10303/4/DasatinibInhibitsHIV-1Replication_2016.pdf
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/10303/7/DasatinibInhibitsHIV-1Replication_2016.pdf.txt
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DasatinibInhibitsHIV-1Replication_2016.pdf.txt