HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles
J.-H. Lee,
C. Ostalecki,
Z. Zhao,
T. Kesti,
H. Bruns,
B. Simon,
T. Harrer,
K. Saksela,
A.S. Baur
Affiliations
J.-H. Lee
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Hartmannstr. 14, 91054 Erlangen, Germany
C. Ostalecki
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Hartmannstr. 14, 91054 Erlangen, Germany
Z. Zhao
Department of Virology, University of Helsinki, PO Box 21, Haartmaninkatu 3, 00014, Finland
T. Kesti
Department of Virology, University of Helsinki, PO Box 21, Haartmaninkatu 3, 00014, Finland
H. Bruns
Department of Internal Medicine V, Haematology and Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Hartmannstr. 14, 91054 Erlangen, Germany
B. Simon
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Hartmannstr. 14, 91054 Erlangen, Germany
T. Harrer
Department for Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen, Germany
K. Saksela
Department of Virology, University of Helsinki, PO Box 21, Haartmaninkatu 3, 00014, Finland
A.S. Baur
Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Hartmannstr. 14, 91054 Erlangen, Germany
HIV-Nef activates the myeloid cell-typical tyrosine kinase Hck, but its molecular role in the viral life cycle is not entirely understood. We found that HIV plasma extracellular vesicles (HIV pEV) containing/10 proteases and Nef also harbor Hck, and analyzed its role in the context of HIV pEV secretion. Myeloid cells required Hck for the vesicle-associated release of ADAM17. This could be induced by the introduction of Nef and implied that HIV targeted Hck for vesicle-associated ADAM17 secretion from a myeloid compartment. The other contents of HIV-pEV, however, including miRNA and effector protein profiles, as well as the presence of haptoglobin suggested hepatocytes as a possible cellular source. HIV liver tissue analysis supported this assumption, revealing induction of Hck translation, evidence for ADAM protease activation and HIV infection. Our findings suggest that HIV targets Hck to induce pro-inflammatory vesicles release and identifies hepatocytes as a possible host cell compartment.
