IL-2 Inducible Kinase ITK is Critical for HIV-1 Infection of Jurkat T-cells

Anika Hain,Mohammad Reza Ahmadian,Carsten Münk,Dieter Häussinger,Saeideh Nakhaei-Rad,Melanie Krämer,Arndt Borkhardt,René M Linka

doi:10.1038/s41598-018-21344-7

Anika Hain, Mohammad Reza Ahmadian + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-21344-7

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Journal: Scientific Reports	Publication Date: Feb 16, 2018
Citations: 7	License type: open-access

Affiliation: Heinrich Heine University Düsseldorf

Abstract

Successful replication of Human immunodeficiency virus (HIV)-1 depends on the expression of various cellular host factors, such as the interleukin-2 inducible T-cell kinase (ITK), a member of the protein family of TEC-tyrosine kinases. ITK is selectively expressed in T-cells and coordinates signaling pathways downstream of the T-cell receptor and chemokine receptors, including PLC-1 activation, Ca2+-release, transcription factor mobilization, and actin rearrangements. The exact role of ITK during HIV-1 infection is still unknown. We analyzed the function of ITK during HIV-1 replication and showed that attachment, fusion of virions with the cell membrane and entry into Jurkat T-cells was inhibited when ITK was knocked down. In contrast, reverse transcription and provirus expression were not affected by ITK deficiency. Inhibited ITK expression did not affect the CXCR4 receptor on the cell surface, whereas CD4 and LFA-1 integrin levels were slightly enhanced in ITK knockdown cells and heparan sulfate (HS) expression was completely abolished in ITK depleted T-cells. However, neither HS expression nor other attachment factors could explain the impaired HIV-1 binding to ITK-deficient cells, which suggests that a more complex cellular process is influenced by ITK or that not yet discovered molecules contribute to restriction of HIV-1 binding and entry.

Highlights

Pharmacological approaches to treating Human immunodeficiency virus (HIV)-1 infection have become increasingly efficient, eradication of the virus in infected individuals remains impossible except in rare circumstances after allogeneic stem-cell transplantation[1]
Because proper T-cell activation is required for HIV-1 infection, a function for inducible T-cell kinase (ITK) as a host factor for HIV-1 replication was expected, and recent studies confirmed a block of HIV-1 at various steps of the viral life cycle after ITK inhibition[7,8,9]
We show that down-regulation of ITK expression via RNA interference (RNAi) led to severely reduced HIV-1 expression and spreading in human Jurkat T-cells as well as reduced membrane fusion of HIV-1 caused by an impaired virus particle attachment

Summary

Introduction

Pharmacological approaches to treating Human immunodeficiency virus (HIV)-1 infection have become increasingly efficient, eradication of the virus in infected individuals remains impossible except in rare circumstances after allogeneic stem-cell transplantation[1]. Because HIV-1 infection requires proper T-cell activation, the need for ITK as a host factor likely is related to its role in integrating signaling pathways downstream of the T-cell receptor and chemokine receptors and regulation of processes important for T-cell activation and differentiation[11,12]. These processes include activation of RHO family GTPases RAC1 and CDC42 and actin polarization[12,13,14,15] and regulation of gene expression[16,17,18] and intracellular calcium signaling[19]. Our goal was to further explore the relevance of ITK for infection of HIV-1 and identify novel interaction partners that could be explored as targets to interfere with viral replication

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