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

Irene Guendel, Sergey Iordanskiy, Gavin C. Sampey, Rachel Van Duyne, Valerie Calvert, Emanuel Petricoin, Mohammed Saifuddin, Kylene Kehn-Hall, Fatah Kashanchi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)257-275
Number of pages19
JournalJournal of NeuroVirology
Volume21
Issue number3
DOIs
StatePublished - 16 Jun 2015
Externally publishedYes

Keywords

  • BTK
  • Cell death
  • HIV-1 replication
  • Host cell protein
  • Inhibitor

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