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

• Published in: Virology (New York, N.Y.) N.Y.), 2013-02, Vol.436 (1), p.235-243
• Main Authors: Schiralli Lester, Gillian M, Akiyama, Hisashi, Evans, Erica, Singh, Juswinder, Gummuluru, Suryaram, Henderson, Andrew J
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; adaptor proteins; CD4 antigen; CD4-Positive T-Lymphocytes - virology; Cell Line, Tumor; Cell Membrane - metabolism; Cell Membrane - virology; Data processing; Gag; gag Gene Products, Human Immunodeficiency Virus - metabolism; Gag protein; HIV; HIV Infections - virology; HIV-1 - genetics; HIV-1 - metabolism; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Infection; Infectious Disease; Interleukin-2 - metabolism; ITK; Itk protein; Jurkat Cells; Kinase inhibitors; Lipid rafts; Lymphocytes T; Membrane Microdomains; Microscopy; Plasma membranes; Polarization; Polymerization; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Replication; Signal Transduction; Tec kinases; Virions; Virus Assembly; Virus Release; Virus Replication
• ISSN: 0042-6822; 1096-0341; 1096-0341
• DOI: 10.1016/j.virol.2012.11.015

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.