{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:41:57Z","timestamp":1780515717301,"version":"3.54.1"},"reference-count":95,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Understanding the underlying molecular interaction during a therapy switch from lopinavir (LPV) to darunavir (DRV) is essential to achieve long-term virological suppression. We investigated the kinetic and structural characteristics of multidrug-resistant South African HIV-1 subtype C protease (HIV-1 PR) during therapy switch from LPV to DRV using enzyme activity and inhibition assay, fluorescence spectroscopy, and molecular dynamic simulation. The HIV-1 protease variants were from clinical isolates with a combination of drug resistance mutations; MUT-1 (M46I, I54V, V82A, and L10F), MUT-2 (M46I, I54V, L76V, V82A, L10F, and L33F), and MUT-3 (M46I, I54V, L76V, V82A, L90M, and F53L). Enzyme kinetics analysis shows an association between increased relative resistance to LPV and DRV with the progressive decrease in the mutant HIV-1 PR variants\u2019 catalytic efficiency. A direct relationship between high-level resistance to LPV and intermediate resistance to DRV with intrinsic changes in the three-dimensional structure of the mutant HIV-1 PR as a function of the multidrug-resistance mutation was observed. In silico analysis attributed these structural adjustments to the multidrug-resistance mutations affecting the LPV and DRV binding landscape. Though DRV showed superiority to LPV, as a lower concentration was needed to inhibit the HIV-1 PR variants, the inherent structural changes resulting from mutations selected during LPV therapy may dynamically shape the DRV treatment outcome after the therapy switch.<\/jats:p>","DOI":"10.3390\/biom11040489","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T15:42:19Z","timestamp":1616600539000},"page":"489","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Acquired HIV-1 Protease Conformational Flexibility Associated with Lopinavir Failure May Shape the Outcome of Darunavir Therapy after Antiretroviral Therapy Switch"],"prefix":"10.3390","volume":"11","author":[{"given":"Simeon","family":"Eche","sequence":"first","affiliation":[{"name":"Discipline of Virology, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7464-1626","authenticated-orcid":false,"given":"Ajit","family":"Kumar","sequence":"additional","affiliation":[{"name":"Discipline of Microbiology, School of Life Sciences, University of KwaZulu-Natal (Westville Campus), Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Sonela","sequence":"additional","affiliation":[{"name":"School of Medicine, Physical and Natural Sciences, University of Rome Tor Vegata, 1-00133 Rome, Italy"},{"name":"Chantal Biya International Reference Center for Research on the Management and Prevention of HIV\/AIDS (CIRCB), Yaound\u00e9 P.O. Box 3077, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Discipline of Virology, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,24]]},"reference":[{"key":"ref_1","unstructured":"UNAIDS (2020). 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