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Biochem Pharmacol. 2016 Apr 15;106:30-45. doi: 10.1016/j.bcp.2016.02.002. Epub 2016 Feb 4.

Dasatinib inhibits HIV-1 replication through the interference of SAMHD1 phosphorylation in CD4+ T cells.

Author information

1
AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain.
2
Retrovirology and Viral Immunopathology Laboratory, AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
3
Laboratory of Molecular Virology, Institute of Human Genetics, Montpellier, France.
4
Infectious Diseases Service, AIDS Research Group, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain.
5
AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: mcoiras@isciii.es.

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.

KEYWORDS:

CD4+ T lymphocytes; Chronic myeloid leukemia; Dasatinib; HIV-1 reservoir; SAMHD1

PMID:
26851491
DOI:
10.1016/j.bcp.2016.02.002
[Indexed for MEDLINE]

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