title: HBZ stimulates brain-derived neurotrophic factor/TrkB autocrine/paracrine signaling to promote survival of human T-cell leukemia virus type 1-Infected T cells.
abstract: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuronal proliferation, survival, and plasticity. These effects occur through autocrine and paracrine signaling events initiated by interactions between secreted BDNF and its high-affinity receptor, TrkB. A BDNF/TrkB autocrine/paracrine signaling loop has additionally been implicated in augmenting the survival of cells representing several human cancers and is associated with poor patient prognosis. Adult T-cell leukemia (ATL) is a fatal malignancy caused by infection with the complex retrovirus human T-cell leukemia virus type 1 (HTLV-1). In this study, we found that the HTLV-1-encoded protein HBZ activates expression of BDNF, and consistent with this effect, BDNF expression is elevated in HTLV-1-infected T-cell lines compared to uninfected T cells. Expression of TrkB is also higher in HTLV-1-infected T-cell lines than in uninfected T cells. Furthermore, levels of both BDNF and TrkB mRNAs are elevated in peripheral blood mononuclear cells (PBMCs) from ATL patients, and ATL patient sera contain higher concentrations of BDNF than sera from noninfected individuals. Finally, chemical inhibition of TrkB signaling increases apoptosis in HTLV-1-infected T cells and reduces phosphorylation of glycogen synthase kinase 3β (GSK-3β), a downstream target in the signaling pathway. These results suggest that HBZ contributes to an active BDNF/TrkB autocrine/paracrine signaling loop in HTLV-1-infected T cells that enhances the survival of these cells.
  
  
  OBJECTIVE
  Infection with human T-cell leukemia virus type 1 (HTLV-1) can cause a rare form of leukemia designated adult T-cell leukemia (ATL). Because ATL patients are unresponsive to chemotherapy, this malignancy is fatal. As a retrovirus, HTLV-1 integrates its genome into a host cell chromosome in order to utilize host factors for replication and expression of viral proteins. However, in infected cells from ATL patients, the viral genome is frequently modified to block expression of all but a single viral protein. This protein, known as HBZ, is therefore believed to modulate cellular pathways necessary for the leukemic state and the chemotherapeutic resistance of the cell. Here we provide evidence to support this hypothesis. We found that HBZ promotes a BDNF/TrkB autocrine/paracrine signaling pathway that is known to enhance the survival and chemotherapeutic resistance of other types of cancer cells. It is possible that inhibition of this pathway may improve treatments for ATL.
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Polakowski
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, USA CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Terol
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, USA.
authors.forename: Kimson
authors.initials: K
authors.lastname: Hoang
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Nash
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Laverdure
authors.affiliation: CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Fort de France, Fort de France, Martinique.
authors.forename: Hélène
authors.initials: H
authors.lastname: Gazon
authors.affiliation: Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Fort de France, Fort de France, Martinique.
authors.forename: Gilda
authors.initials: G
authors.lastname: Belrose
authors.affiliation: CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Mesnard
authors.affiliation: Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Fort de France, Fort de France, Martinique.
authors.forename: Raymond
authors.initials: R
authors.lastname: Césaire
authors.affiliation: CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Péloponèse
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, North Carolina, USA lemassoni@ecu.edu.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lemasson
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002470:Cell Survival; D002472:Cell Transformation, Viral; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020813:Receptor, trkB; D012191:Retroviridae Proteins; D013601:T-Lymphocytes / Q000502:physiology / Q000821:virology*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D019208:Brain-Derived Neurotrophic Factor; C479751:HBZ protein, human T-cell leukemia virus type I; D008562:Membrane Glycoproteins; D012191:Retroviridae Proteins; D014764:Viral Proteins; C579455:BDNF protein, human; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human