Selective targeting of ITK blocks multiple steps of HIV replication

Julie A. Readinger, Gillian M. Schiralli, Jian Kang Jiang, Craig J. Thomas, Avery August, Andrew J. Henderson, Pamela L. Schwartzberg

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Treatment for HIV has relied on the use of antiretroviral agents that can be subject to the development of resistant viruses. The study of inhibitors directed against cellular proteins required for HIV replication is therefore of growing interest. Inducible T cell kinase (ITK) is a Tec family tyrosine kinase that regulates T cell receptor (TCR)-induced activation of PLCγ-1, Ca 2+ mobilization and transcription factor activation, and actin rearrangement downstream of both TCR and chemokine receptors. Because productive infection of T cells with HIV requires T cell activation, chemokine receptors and actin reorganization, we asked whether ITK affects HIV infection using ITK-specific siRNA, a kinase-inactive ITK mutant or an ITK inhibitor. We demonstrate that loss of ITK function resulted in marked reductions in intracellular p24 levels upon HIV infection. Loss of ITK function after establishment of HIV infection also decreased virus spread within the culture. Inhibition of ITK did not affect expression of the HIV coreceptors CD4 or CXCR4 but partially blocked HIV viral entry, an effect that correlated with decreased actin polarization to gp120. Additionally, ITK was required for efficient HIV transcription, and overexpression of ITK increased both viral transcription and virus-like particle formation. Our data suggest that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication.

Original languageEnglish (US)
Pages (from-to)6684-6689
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number18
DOIs
StatePublished - May 6 2008

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Selective targeting of ITK blocks multiple steps of HIV replication'. Together they form a unique fingerprint.

Cite this