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Role of Bruton’s tyrosine kinase inhibitors in HIV-1-infected cells

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Abstract

Many cellular cofactors have been documented to be critical for various stages of viral replication. Using high-throughput proteomic assays, we have previously identified Bruton’s tyrosine kinase (BTK) as a host protein that was uniquely upregulated in the plasma membrane of human immunodeficiency virus (HIV-1)-infected T cells. Here, we have further characterized the BTK expression in HIV-1 infection and show that this cellular factor is specifically expressed in infected myeloid cells. Significant upregulation of the phosphorylated form of BTK was observed in infected cells. Using size exclusion chromatography, we found BTK to be virtually absent in the uninfected U937 cells; however, new BTK protein complexes were identified and distributed in both high molecular weight (∼600 kDa) and a small molecular weight complex (∼60–120 kDa) in the infected U1 cells. BTK levels were highest in cells either chronically expressing virus or induced/infected myeloid cells and that BTK translocated to the membrane following induction of the infected cells. BTK knockdown in HIV-1-infected cells using small interfering RNA (siRNA) resulted in selective death of infected, but not uninfected, cells. Using BTK-specific antibody and small-molecule inhibitors including LFM-A13 and a FDA-approved compound, ibrutinib (PCI-32765), we have found that HIV-1-infected cells are sensitive to apoptotic cell death and result in a decrease in virus production. Overall, our data suggests that HIV-1-infected cells are sensitive to treatments targeting BTK expressed in infected cells.

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Acknowledgments

We would like to thank the members of the Kashanchi Lab for experiments and assistance with the manuscript, and the NIH AIDS Research and Reference Reagent Program for the contribution of the important reagents. This work was supported by National Institutes of Health grant AI070740, AI043894, AI11340, and AI114490 to FK and a grant from Virginia’s Commonwealth Health Research Board to KK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, 20110, USA

    Irene Guendel, Sergey Iordanskiy, Gavin C. Sampey, Kylene Kehn-Hall & Fatah Kashanchi

  2. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA

    Rachel Van Duyne

  3. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA

    Valerie Calvert & Emanuel Petricoin

  4. WuXi AppTec, Inc., Philadelphia, PA, 19112, USA

    Mohammed Saifuddin

  5. Laboratory of Molecular Virology, George Mason University, Discovery Hall, Room 182, 10900 University Blvd. MS 1H8, Manassas, VA, 20110, USA

    Fatah Kashanchi

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  1. Irene Guendel
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  2. Sergey Iordanskiy
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  9. Fatah Kashanchi
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Correspondence to Fatah Kashanchi.

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Irene Guendel and Sergey Iordanskiy contributed equally to this work.

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Guendel, I., Iordanskiy, S., Sampey, G.C. et al. Role of Bruton’s tyrosine kinase inhibitors in HIV-1-infected cells. J. Neurovirol. 21, 257–275 (2015). https://doi.org/10.1007/s13365-015-0323-5

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