{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T21:56:25Z","timestamp":1753739785506,"version":"3.37.3"},"reference-count":34,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,1,31]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>HIV protease is essential for processing the Gag polyprotein to produce infectious virions and is a major target in antiretroviral therapy. We have identified an unusual HIV-1 subtype C variant that contains insertions of leucine and asparagine (L38\u2191N\u2191L) in the hinge region of protease at position 38. This was isolated from a protease inhibitor na\u00efve infant. Isothermal titration calorimetry showed that 10% less of L38\u2191N\u2191L protease was in the active conformation as compared with a reference strain. L38\u2191N\u2191L protease displayed a \u00b150% reduction in KM and kcat. The catalytic efficiency (kcat\/KM) of L38\u2191N\u2191L protease was not significantly different from that of wild type although there was a 42% reduction in specific activity for the variant. An in vitro phenotypic assay showed the L38\u2191N\u2191L protease to be susceptible to lopinavir (LPV), atazanavir (ATV) and darunavir in the context of an unrelated Gag. However, in the presence of the related Gag, L38\u2191N\u2191L showed reduced susceptibility to darunavir while remaining susceptible to LPV and ATV. Furthermore, a reduction in viral replication capacity (RC) was observed in combination with the related Gag. The reduced susceptibility to darunavir and decrease in RC may be due to PTAPP duplication in the related Gag. The present study shows the importance of considering the Gag region when looking at drug susceptibility of HIV-1 protease variants.<\/jats:p>","DOI":"10.1042\/bcj20180692","type":"journal-article","created":{"date-parts":[[2018,12,20]],"date-time":"2018-12-20T21:35:11Z","timestamp":1545341711000},"page":"375-384","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Double trouble? Gag in conjunction with double insert in HIV protease contributes to reduced DRV susceptibility"],"prefix":"10.1042","volume":"476","author":[{"given":"Alison","family":"Williams","sequence":"first","affiliation":[{"name":"Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg 2050, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriaan","family":"Basson","sequence":"additional","affiliation":[{"name":"Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Services (NHLS), Johannesburg, South Africa"},{"name":"HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193 Johannesburg, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikechukwu","family":"Achilonu","sequence":"additional","affiliation":[{"name":"Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg 2050, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heini W.","family":"Dirr","sequence":"additional","affiliation":[{"name":"Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg 2050, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn","family":"Morris","sequence":"additional","affiliation":[{"name":"Centre for HIV and STIs, National Institute for Communicable Diseases (NICD) of the National Health Laboratory Services (NHLS), Johannesburg, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1781-2115","authenticated-orcid":false,"given":"Yasien","family":"Sayed","sequence":"additional","affiliation":[{"name":"Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg 2050, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2019,1,31]]},"reference":[{"volume-title":"Global Report: UNAIDS Report on Global AIDS Epidemic 2016","year":"2016","author":"UNAIDS","key":"2021112217543580400_BCJ-2018-0692C1"},{"key":"2021112217543580400_BCJ-2018-0692C2","doi-asserted-by":"publisher","first-page":"S7","DOI":"10.1002\/jmv.20599","article-title":"Global epidemiology of HIV","volume":"78","year":"2006","journal-title":"J. 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