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BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu\u2019s polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1\u2019s immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1.<\/jats:p>","DOI":"10.1128\/mbio.01113-19","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T11:01:58Z","timestamp":1560769318000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses"],"prefix":"10.1128","volume":"10","author":[{"given":"J\u00e9r\u00e9mie","family":"Pr\u00e9vost","sequence":"first","affiliation":[{"name":"Centre de Recherche du CHUM, Montreal, Quebec, Canada"},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al, Montreal, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Pickering","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, King\u2019s College London School of Life Sciences and Medicine, Guy\u2019s Hospital, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell J.","family":"Mumby","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halima","family":"Medjahed","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Gendron-Lepage","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria G.","family":"Delgado","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brennan S.","family":"Dirk","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy D.","family":"Dikeakos","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"St\u00fcrzel","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Sauter","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Kirchhoff","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Bibollet-Ruche","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice H.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Dub\u00e9","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM, Montreal, Quebec, Canada"},{"name":"Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"},{"name":"Center for HIV\/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J. 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