title: Role of Bruton's tyrosine kinase inhibitors in HIV-1-infected cells.
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.
authors: Department of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, 20110, USA.
authors: Irene
authors: I
authors: Guendel
authors: Sergey
authors: S
authors: Iordanskiy
authors: Gavin C
authors: GC
authors: Sampey
authors: Rachel
authors: R
authors: Van Duyne
authors: Valerie
authors: V
authors: Calvert
authors: Emanuel
authors: E
authors: Petricoin
authors: Mohammed
authors: M
authors: Saifuddin
authors: Kylene
authors: K
authors: Kehn-Hall
authors: Fatah
authors: F
authors: Kashanchi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1; D057166:High-Throughput Screening Assays; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D040901:Proteomics; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000577:Amides; C118451:LFM A13; D009570:Nitriles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine