title: HIV-Nef and ADAM17-Containing Plasma Extracellular Vesicles Induce and Correlate with Immune Pathogenesis in Chronic HIV Infection.
abstract: Antiretroviral therapy (ART) efficiently suppresses HIV replication but immune activation and low CD4 T cell counts often persist. The underlying mechanism of this ART-resistant pathogenesis is not clear. We observed that levels of plasma extracellular vesicles (pEV) are strongly elevated in HIV infection and do not decline during ART. Surprisingly, these vesicles contained the viral accessory proteins Nef and Vpu, which are assumed to be not expressed under efficient ART, as well as pro-inflammatory effectors, including activated ADAM17. HIV pEV were characterized by the presence of activated αvβ3 and absence of CD81 and Tsg101. Correlating with immune activation, peripheral monocytes ingested large amounts of pEV, giving rise to an increased population of CD1c(+) CD14(+) cells that secreted inflammatory cytokines. Importantly, the pro-inflammatory content, particularly ADAM17 activity, correlated with low T cell counts. Preliminary evidence suggested that HIV pEV derived from peripheral mononuclear cells and from an unknown myeloid cell population. In summary we propose an important role of pro-inflammatory pEV in chronic HIV infection due to ongoing viral Nef activity.
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schierer
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Blume
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Dindorf
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wittki
authors.affiliation: Department for Biochemistry and Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Fahrstraße 17, 91054 Erlangen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ostalecki
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Straße 68, 51429 Bergisch Gladbach, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Koliha
authors.affiliation: Miltenyi Biotec GmbH, Friedrich-Ebert-Straße 68, 51429 Bergisch Gladbach, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wild
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany.
authors.forename: Gerold
authors.initials: G
authors.lastname: Schuler
authors.affiliation: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
authors.affiliation: Department of Virology, 00014 University of Helsinki, PO Box 21, Haartmaninkatu 3, Finland.
authors.forename: Kalle
authors.initials: K
authors.lastname: Saksela
authors.affiliation: Department for Internal Medicine 3, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrer
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Translational Research Center, Ulmenweg 12, 91054 Erlangen, Germany. Electronic address: andreas.baur@uk-erlangen.de.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Baur
mesh_terms: D000072198:ADAM17 Protein / Q000276:immunology*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D000067128:Extracellular Vesicles / Q000187:drug effects / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018655:Lymphocyte Count; D013601:T-Lymphocytes / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D054311:nef Gene Products, Human Immunodeficiency Virus; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ADAM17; Chronic HIV infection; Extracellular vesicles; HIV; HIV reservoir; Nef; Vpu