title: HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection.
abstract: Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes. Key event was the Nef-mediated routing of the TNF-converting enzyme ADAM17 into Rab4+ early endosomes and the Rab27+ secretory pathway. Analysis of lymph-node tissue by multi-epitope-ligand-cartography (MELC) confirmed a vesicular TNF secretion phenotype that co-localized with persistent Nef expression, and implicated Notch1 as an essential co-factor. Surprisingly Notch1 had no transcriptional effect but was required for the endosomal trafficking of ADAM17. We conclude that Nef expression and Nef-containing pEV mobilize TNF from endosomal compartments in acute and chronic infection.
authors: Department of Dermatology, University Hospital Erlangen, Hartmannstr. 14, 91054 Erlangen, Germany.
authors: Christian
authors: C
authors: Ostalecki
authors: Department of Dermatology, University Hospital Erlangen, Hartmannstr. 14, 91054 Erlangen, Germany.
authors: Sebastian
authors: S
authors: Wittki
authors: Department of Dermatology, University Hospital Erlangen, Hartmannstr. 14, 91054 Erlangen, Germany.
authors: Jung-Hyun
authors: JH
authors: Lee
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.
authors: Miriam M
authors: MM
authors: Geist
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.
authors: Nadine
authors: N
authors: Tibroni
authors: Department for Internal Medicine 3, University Hospital Erlangen, Ulmenweg 18, Erlangen, Germany.
authors: Thomas
authors: T
authors: Harrer
authors: Department of Dermatology, University Hospital Erlangen, Hartmannstr. 14, 91054 Erlangen, Germany.
authors: Gerold
authors: G
authors: Schuler
authors: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.
authors: Oliver T
authors: OT
authors: Fackler
authors: Department of Dermatology, University Hospital Erlangen, Hartmannstr. 14, 91054 Erlangen, Germany. Electronic address: andreas.baur@uk-erlangen.de.
authors: Andreas S
authors: AS
authors: Baur
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D002908:Chronic Disease; D004705:Endocytosis / Q000276:immunology*; D011992:Endosomes / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051881:Receptor, Notch1 / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology* / Q000378:metabolism; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051881:Receptor, Notch1; D048069:Tumor Necrosis Factors; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D000072198:ADAM17 Protein; D020695:rab4 GTP-Binding Proteins
keywords: ADAM17; Endosomal secretion; HIV Nef; Notch1; Plasma extracellular vesicles