Interleukin 2-inducible T cell kinase (ITK) facilitates efficient egress of HIV-1 by coordinating Gag distribution and actin organization

Virology. 2013 Feb 5;436(1):235-43. doi: 10.1016/j.virol.2012.11.015. Epub 2012 Dec 20.

Abstract

Interleukin 2-inducible T cell kinase (ITK) influences T cell signaling by coordinating actin polymerization and polarization as well as recruitment of kinases and adapter proteins. ITK regulates multiple steps of HIV-1 replication, including virion assembly and release. Fluorescent microscopy was used to examine the functional interactions between ITK and HIV-1 Gag during viral particle release. ITK and Gag colocalized at the plasma membrane and were concentrated at sites of F-actin accumulation and membrane lipid rafts in HIV-1 infected T cells. There was polarized staining of ITK, Gag, and actin towards sites of T cell conjugates. Small molecule inhibitors of ITK disrupted F-actin capping, perturbed Gag-ITK colocalization, inhibited virus like particle release, and reduced HIV replication in primary human CD4+ T cells. These data provide insight as to how ITK influences HIV-1 replication and suggest that targeting host factors that regulate HIV-1 egress provides an innovative strategy for controlling HIV infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism*
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Membrane / virology
  • HIV Infections / virology
  • HIV-1 / genetics
  • HIV-1 / metabolism
  • HIV-1 / physiology*
  • Humans
  • Interleukin-2 / metabolism
  • Jurkat Cells
  • Membrane Microdomains
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Virus Assembly
  • Virus Release
  • Virus Replication
  • gag Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Actins
  • Interleukin-2
  • gag Gene Products, Human Immunodeficiency Virus
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase