title: Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein.
abstract: Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The HTLV-1 transactivator protein Tax controls many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Extracellular vesicles called exosomes play critical roles during pathogenic viral infections as delivery vehicles for host and viral components, including proteins, mRNA, and microRNA. We hypothesized that exosomes derived from HTLV-1-infected cells contain unique host and viral proteins that may contribute to HTLV-1-induced pathogenesis. We found exosomes derived from infected cells to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. Finally, IL-2-dependent CTLL-2 cells that received Tax-containing exosomes were protected from apoptosis through activation of AKT. Similar experiments with primary cultures showed protection and survival of peripheral blood mononuclear cells even in the absence of phytohemagglutinin/IL-2. Surviving cells contained more phosphorylated Rb, consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells.
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jaworski
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Narayanan
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110, the Department of Microbiology, Immunology, and Tropical Medicine and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Van Duyne
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110.
authors.forename: Shabana
authors.initials: S
authors.lastname: Shabbeer-Meyering
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110, the Department of Microbiology, Immunology, and Tropical Medicine and.
authors.forename: Sergey
authors.initials: S
authors.lastname: Iordanskiy
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Saifuddin
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110.
authors.forename: Ravi
authors.initials: R
authors.lastname: Das
authors.affiliation: the Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, F-75015 Paris, France, CNRS, UMR3569, F-75015 Paris, France, and.
authors.forename: Philippe V
authors.initials: PV
authors.lastname: Afonso
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Sampey
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110.
authors.forename: Myung
authors.initials: M
authors.lastname: Chung
authors.affiliation: the Department of Chemistry, George Washington University, Washington, D. C. 20037.
authors.forename: Anastas
authors.initials: A
authors.lastname: Popratiloff
authors.affiliation: Center for Microscopy and Image Analysis, George Washington University Medical Center, Washington, D. C. 20037.
authors.forename: Bindesh
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: the Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Doylestown, Pennsylvania 18902.
authors.forename: Mohit
authors.initials: M
authors.lastname: Sehgal
authors.affiliation: the Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Doylestown, Pennsylvania 18902.
authors.forename: Pooja
authors.initials: P
authors.lastname: Jain
authors.affiliation: Center for Microscopy and Image Analysis, George Washington University Medical Center, Washington, D. C. 20037.
authors.forename: Akos
authors.initials: A
authors.lastname: Vertes
authors.affiliation: the Equipe Oncogenèse Rétrovirale, Equipe labelisée "Ligue Nationale Contre le Cancer," International Center for Research in Infectiology, INSERM U1111-CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon 1, Lyon 69364 Cedex 07, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Mahieux
authors.affiliation: From the School of Systems Biology, National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, Virginia 20110, fkashanc@gmu.edu.
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology / Q000821:virology; D055354:Exosomes / Q000378:metabolism / Q000821:virology; D016356:Gene Products, tax / Q000276:immunology / Q000378:metabolism*; D015490:HTLV-I Infections / Q000209:etiology / Q000503:physiopathology / Q000821:virology; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D014774:Virulence; D019014:fas Receptor / Q000037:antagonists & inhibitors
chemical_list: D016356:Gene Products, tax; D019014:fas Receptor; C514970:tax protein, Human T-lymphotrophic virus 1
keywords: Biomarker; Cytokine Induction; Exosome; HTLV-1 Infection; Leukemia; Oncogene; Tax Protein; Transactivation