{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:52:17Z","timestamp":1785214337251,"version":"3.55.0"},"reference-count":67,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,26]],"date-time":"2024-05-26T00:00:00Z","timestamp":1716681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases (NIH NIAID)","award":["R01 AI140847"],"award-info":[{"award-number":["R01 AI140847"]}]},{"name":"National Institute of Allergy and Infectious Diseases (NIH NIAID)","award":["T32 AI127201"],"award-info":[{"award-number":["T32 AI127201"]}]},{"name":"NIH NIAID","award":["R01 AI140847"],"award-info":[{"award-number":["R01 AI140847"]}]},{"name":"NIH NIAID","award":["T32 AI127201"],"award-info":[{"award-number":["T32 AI127201"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>HIV-1 protease inhibitors are an essential component of antiretroviral therapy. However, drug resistance is a pervasive issue motivating a persistent search for novel therapies. Recent reports found that when protease activates within the host cell\u2019s cytosol, it facilitates the pyroptotic killing of infected cells. This has led to speculation that promoting protease activation, rather than inhibiting it, could help to eradicate infected cells and potentially cure HIV-1 infection. Here, we used a nanoscale flow cytometry-based assay to characterize protease resistance mutations and polymorphisms. We quantified protease activity, viral concentration, and premature protease activation and confirmed previous findings that major resistance mutations generally destabilize the protease structure. Intriguingly, we found evidence that common polymorphisms in the hinge domain of protease can influence its susceptibility to premature activation. This suggests that viral heterogeneity could pose a considerable challenge for therapeutic strategies aimed at inducing premature protease activation in the future.<\/jats:p>","DOI":"10.3390\/v16060849","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:14:07Z","timestamp":1716804847000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Premature Activation of the HIV-1 Protease Is Influenced by Polymorphisms in the Hinge Region"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9503-4673","authenticated-orcid":false,"given":"Caroline O.","family":"Tabler","sequence":"first","affiliation":[{"name":"Center for Proteomics and Bioinformatics, Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Wegman","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Bioinformatics, Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najwa","family":"Alhusaini","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Bioinformatics, Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8844-8502","authenticated-orcid":false,"given":"Nicole F.","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Bioinformatics, Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Tilton","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Bioinformatics, Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1006\/jmbi.1998.2090","article-title":"The Structural Stability of the HIV-1 Protease","volume":"283","author":"Todd","year":"1998","journal-title":"J. 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