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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / virology
  • Cell Proliferation / drug effects
  • Dasatinib / pharmacology*
  • Female
  • Gene Expression Regulation
  • HIV Infections / drug therapy*
  • HIV Infections / enzymology
  • HIV Infections / genetics
  • HIV Infections / virology
  • HIV-1 / drug effects
  • HIV-1 / genetics
  • HIV-1 / growth & development
  • Host-Pathogen Interactions
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Lymphocyte Activation
  • Male
  • Monomeric GTP-Binding Proteins / antagonists & inhibitors*
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • SAM Domain and HD Domain-Containing Protein 1
  • Signal Transduction
  • Vesiculovirus / genetics
  • Viral Fusion Proteins / genetics
  • Viral Fusion Proteins / metabolism
  • Virus Internalization / drug effects
  • Virus Replication / drug effects*

Substances

  • Anti-HIV Agents
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Viral Fusion Proteins
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Monomeric GTP-Binding Proteins
  • Dasatinib