{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:15:58Z","timestamp":1790835358257,"version":"4.1.0"},"reference-count":69,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T00:00:00Z","timestamp":1649980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 AI4046747"],"award-info":[{"award-number":["R21 AI4046747"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>HIV-1 Vpu targets the host cell proteins CD4 and BST-2\/Tetherin for degradation, ultimately resulting in enhanced virus spread and host immune evasion. The discovery and characterization of small molecules that antagonize Vpu would further elucidate the contribution of Vpu to pathogenesis and lay the foundation for the study of a new class of novel HIV-1 therapeutics. To identify novel compounds that block Vpu activity, we have developed a cell-based \u2018gain of function\u2019 assay that produces a positive signal in response to Vpu inhibition. To develop this assay, we took advantage of the viral glycoprotein, GaLV Env. In the presence of Vpu, GaLV Env is not incorporated into viral particles, resulting in non-infectious virions. Vpu inhibition restores infectious particle production. Using this assay, a high throughput screen of &gt;650,000 compounds was performed to identify inhibitors that block the biological activity of Vpu. From this screen, we identified several positive hits but focused on two compounds from one structural family, SRI-41897 and SRI-42371. We developed independent counter-screens for off target interactions of the compounds and found no off target interactions. Additionally, these compounds block Vpu-mediated modulation of CD4, BST-2\/Tetherin and antibody dependent cell-mediated toxicity (ADCC). Unfortunately, both SRI-41897 and SRI-42371 were shown to be specific to the N-terminal region of NL4-3 Vpu and did not function against other, more clinically relevant, strains of Vpu; however, this assay may be slightly modified to include more significant Vpu strains in the future.<\/jats:p>","DOI":"10.3390\/v14040817","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:22:43Z","timestamp":1650414163000},"page":"817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel Compound Inhibitors of HIV-1NL4-3 Vpu"],"prefix":"10.3390","volume":"14","author":[{"given":"Carolyn A.","family":"Robinson","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, School of Medicine and the Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terri D.","family":"Lyddon","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, School of Medicine and the Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3722-4302","authenticated-orcid":false,"given":"Hwi Min","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3089-0601","authenticated-orcid":false,"given":"Yury V.","family":"Kuzmichev","sequence":"additional","affiliation":[{"name":"Infectious Disease Research, Drug Development Division, Southern Research, Frederick, MD 21701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Richard","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM, Montr\u00e9al, QC HX2 0A9, Canada"},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC HX2 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Finzi","sequence":"additional","affiliation":[{"name":"Centre de Recherche du CHUM, Montr\u00e9al, QC HX2 0A9, Canada"},{"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC HX2 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2932-1436","authenticated-orcid":false,"given":"Sarah","family":"Welbourn","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, School of Medicine and the Christopher S. 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Bond Life Sciences Center, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"F59","DOI":"10.1097\/00002030-199905280-00001","article-title":"Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy","volume":"13","author":"Harrigan","year":"1999","journal-title":"AIDS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s10875-009-9275-y","article-title":"CD8+ cell anti-HIV activity rapidly increases upon discontinuation of early antiretroviral therapy","volume":"29","author":"Killian","year":"2009","journal-title":"J. Clin. 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