{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:50:00Z","timestamp":1791345000710,"version":"4.3.1"},"reference-count":79,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1P01GM109767-01A`"],"award-info":[{"award-number":["1P01GM109767-01A`"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01-GM135919"],"award-info":[{"award-number":["R01-GM135919"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["R01-AI140970"],"award-info":[{"award-number":["R01-AI140970"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100011072","name":"UNC CFAR","doi-asserted-by":"crossref","award":["P30-AI050410"],"award-info":[{"award-number":["P30-AI050410"]}],"id":[{"id":"10.13039\/100011072","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008615","name":"UNC Lineberger Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["P30-CA016086"],"award-info":[{"award-number":["P30-CA016086"]}],"id":[{"id":"10.13039\/100008615","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,14]]},"abstract":"<jats:p>Darunavir (DRV) is exceptional among potent HIV-1 protease inhibitors (PIs) in high drug concentrations that are achieved in vivo. Little is known about the de novo resistance pathway for DRV. We selected for resistance to high drug concentrations against 10 PIs and their structural precursor DRV. Mutations accumulated through two pathways (anchored by protease mutations I50V or I84V). Small changes in the inhibitor P1'-equivalent position led to preferential use of one pathway over the other. Changes in the inhibitor P2'-equivalent position determined differences in potency that were retained in the resistant viruses and that impacted the selected mutations. Viral variants from the two pathways showed differential selection of compensatory mutations in Gag cleavage sites. These results reveal the high level of selective pressure that is attainable with fifth-generation PIs and how features of the inhibitor affect both the resistance pathway and the residual potency in the face of resistance.<\/jats:p>","DOI":"10.7554\/elife.80328","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T09:00:47Z","timestamp":1678870847000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.80328","source":"Crossref","is-referenced-by-count":18,"title":["Selection of HIV-1 for resistance to fifth-generation protease inhibitors reveals two independent pathways to high-level resistance"],"prefix":"10.7554","volume":"12","author":[{"given":"Ean","family":"Spielvogel","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]},{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sook-Kyung","family":"Lee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuntai","family":"Zhou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon J","family":"Lockbaum","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Henes","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Sondgeroth","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]},{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klajdi","family":"Kosovrasti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen A","family":"Nalivaika","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akbar","family":"Ali","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nese Kurt","family":"Yilmaz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2270-6613","authenticated-orcid":true,"given":"Celia A","family":"Schiffer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School","place":["Worcester, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7777-0773","authenticated-orcid":true,"given":"Ronald","family":"Swanstrom","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]},{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill","place":["Chapel Hill, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"2509","DOI":"10.3390\/v2112509","article-title":"Molecular basis for drug resistance in HIV-1 protease","volume":"2","author":"Ali","year":"2010","journal-title":"Viruses"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1128\/AAC.01413-06","article-title":"A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro","volume":"51","author":"Amano","year":"2007","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1097\/QAD.0000000000000778","article-title":"Week 48 efficacy and central nervous system analysis of darunavir\/ritonavir monotherapy versus darunavir\/ritonavir with two nucleoside analogues","volume":"29","author":"Antinori","year":"2015","journal-title":"AIDS"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.28020","article-title":"A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented am to pm potency","volume":"6","author":"Aoki","year":"2017","journal-title":"eLife"},{"key":"bib5","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02425-17","article-title":"Mechanism of darunavir (DRV)\u2019s high genetic barrier to HIV-1 resistance: a key V32I substitution in protease rarely occurs, but once it occurs, it predisposes HIV-1 to develop DRV resistance","volume":"9","author":"Aoki","year":"2018","journal-title":"MBio"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1111\/j.1468-1293.2012.00989.x","article-title":"The MONET trial: week 144 analysis of the efficacy of darunavir\/ritonavir (DRV\/r) monotherapy versus DRV\/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load < 50 HIV-1 RNA copies\/ml at baseline","volume":"13","author":"Arribas","year":"2012","journal-title":"HIV Medicine"},{"key":"bib7","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-65993-z","article-title":"Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity","volume":"10","author":"Bulut","year":"2020","journal-title":"Scientific Reports"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1177\/0956462419896478","article-title":"Maintenance of virologic suppression and improvement in comorbidities after simplification to raltegravir plus boosted darunavir among treatment-experienced HIV-infected patients","volume":"31","author":"Casado","year":"2020","journal-title":"International Journal of STD & AIDS"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.jmb.2006.07.073","article-title":"Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring","volume":"363","author":"Cihlar","year":"2006","journal-title":"Journal of Molecular Biology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"12141","DOI":"10.1021\/bi049459m","article-title":"Comparing the accumulation of active- and nonactive-site mutations in the HIV-1 protease","volume":"43","author":"Clemente","year":"2004","journal-title":"Biochemistry"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1089\/aid.2007.0173","article-title":"Resistance profile of darunavir: combined 24-week results from the power trials","volume":"24","author":"de Meyer","year":"2008","journal-title":"AIDS Research and Human Retroviruses"},{"key":"bib12","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02060-17","article-title":"GRL-079, a novel HIV-1 protease inhibitor, is extremely potent against multidrug-resistant HIV-1 variants and has a high genetic barrier against the emergence of resistant variants","volume":"62","author":"Delino","year":"2018","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1093\/jac\/dkn544","article-title":"Mutations associated with virological response to darunavir\/ritonavir in HIV-1-infected protease inhibitor-experienced patients","volume":"63","author":"Descamps","year":"2009","journal-title":"The Journal of Antimicrobial Chemotherapy"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1080\/25787489.2020.1734752","article-title":"96-week results of a dual therapy with darunavir\/ritonavir plus rilpivirine once a day vs triple therapy in patients with suppressed viraemia: virological success and non-HIV related morbidity evaluation","volume":"21","author":"Di Cristo","year":"2020","journal-title":"HIV Research & Clinical Practice"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.str.2007.01.006","article-title":"Hydrophobic sliding: a possible mechanism for drug resistance in human immunodeficiency virus type 1 protease","volume":"15","author":"Foulkes-Murzycki","year":"2007","journal-title":"Structure"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/s0960-894x(98)00098-5","article-title":"Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino) sulfonamide isostere","volume":"8","author":"Ghosh","year":"1998","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1002\/cmdc.200600103","article-title":"Bis-Tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistance","volume":"1","author":"Ghosh","year":"2006","journal-title":"ChemMedChem"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1021\/ar7001232","article-title":"Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance","volume":"41","author":"Ghosh","year":"2008","journal-title":"Accounts of Chemical Research"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"4267","DOI":"10.1021\/acs.jmedchem.7b00172","article-title":"Design and development of highly potent HIV-1 protease inhibitors with a crown-like oxotricyclic core as the P2-ligand to combat multidrug-resistant HIV variants","volume":"60","author":"Ghosh","year":"2017","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"4561","DOI":"10.1021\/acs.jmedchem.8b00298","article-title":"Design and synthesis of highly potent HIV-1 protease inhibitors containing tricyclic fused ring systems as novel P2 ligands: structure-activity studies, biological and X-ray structural analysis","volume":"61","author":"Ghosh","year":"2018","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1002\/cmdc.201700824","article-title":"Design of highly potent, dual-acting and central-nervous-system-penetrating HIV-1 protease inhibitors with excellent potency against multidrug-resistant HIV-1 variants","volume":"13","author":"Ghosh","year":"2018","journal-title":"ChemMedChem"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"4867","DOI":"10.1021\/acs.jmedchem.0c00202","article-title":"Structure-Based design of highly potent HIV-1 protease inhibitors containing new tricyclic ring P2-ligands: design, synthesis, biological, and X-ray structural studies","volume":"63","author":"Ghosh","year":"2020","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1056\/NEJM199709113371102","article-title":"Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy","volume":"337","author":"Gulick","year":"1997","journal-title":"The New England Journal of Medicine"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"513","DOI":"10.3851\/IMP3330","article-title":"Boosted darunavir and dolutegravir dual therapy among a cohort of highly treatment-experienced individuals","volume":"24","author":"Hawkins","year":"2019","journal-title":"Antiviral Therapy"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"3147","DOI":"10.1128\/AAC.00401-07","article-title":"In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV","volume":"51","author":"Hazen","year":"2007","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1128\/AAC.05549-11","article-title":"Interplay between single resistance-associated mutations in the HIV-1 protease and viral infectivity, protease activity, and inhibitor sensitivity","volume":"56","author":"Henderson","year":"2012","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1021\/acschembio.9b00370","article-title":"Picomolar to micromolar: elucidating the role of distal mutations in HIV-1 protease in conferring drug resistance","volume":"14","author":"Henes","year":"2019","journal-title":"ACS Chemical Biology"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01225","article-title":"Efficacy and safety of raltegravir-based dual therapy in AIDS patients: a meta-analysis of randomized controlled trials","volume":"10","author":"Huang","year":"2019","journal-title":"Frontiers in Pharmacology"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/BF01028194","article-title":"Large scale purification and refolding of HIV-1 protease from Escherichia coli inclusion bodies","volume":"12","author":"Hui","year":"1993","journal-title":"Journal of Protein Chemistry"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/329654a0","article-title":"Inhibition of retroviral protease activity by an aspartyl proteinase inhibitor","volume":"329","author":"Katoh","year":"1987","journal-title":"Nature"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1110\/ps.25502","article-title":"Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease","volume":"11","author":"King","year":"2002","journal-title":"Protein Science"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1016\/j.chembiol.2004.08.010","article-title":"Combating susceptibility to drug resistance: lessons from HIV-1 protease","volume":"11","author":"King","year":"2004","journal-title":"Chemistry & Biology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"11961","DOI":"10.1128\/JVI.00967-10","article-title":"In vitro selection of highly darunavir-resistant and replication-competent HIV-1 variants by using a mixture of clinical HIV-1 isolates resistant to multiple conventional protease inhibitors","volume":"84","author":"Koh","year":"2010","journal-title":"Journal of Virology"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/j.virol.2005.11.049","article-title":"Co-Evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate","volume":"347","author":"Kolli","year":"2006","journal-title":"Virology"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"11027","DOI":"10.1128\/JVI.00628-09","article-title":"Human immunodeficiency virus type 1 protease-correlated cleavage site mutations enhance inhibitor resistance","volume":"83","author":"Kolli","year":"2009","journal-title":"Journal of Virology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"7145","DOI":"10.1128\/JVI.00266-14","article-title":"Hiv-1 protease-substrate coevolution in nelfinavir resistance","volume":"88","author":"Kolli","year":"2014","journal-title":"Journal of Virology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1021\/jm050943c","article-title":"Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M","volume":"49","author":"Kovalevsky","year":"2006","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1089\/aid.2008.0216","article-title":"Darunavir concentrations in cerebrospinal fluid and blood in HIV-1-infected individuals","volume":"25","author":"Kurt Yilmaz","year":"2009","journal-title":"AIDS Research and Human Retroviruses"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"13279","DOI":"10.1074\/jbc.M112.339374","article-title":"Context surrounding processing sites is crucial in determining cleavage rate of a subset of processing sites in HIV-1 Gag and Gag-Pro-Pol polyprotein precursors by viral protease","volume":"287","author":"Lee","year":"2012","journal-title":"The Journal of Biological Chemistry"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.1021\/acs.jctc.0c01244","article-title":"Deciphering complex mechanisms of resistance and loss of potency through coupled molecular dynamics and machine learning","volume":"17","author":"Leidner","year":"2021","journal-title":"Journal of Chemical Theory and Computation"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1006\/abio.1998.3014","article-title":"Use of a fluorescence plate reader for measuring kinetic parameters with inner filter effect correction","volume":"267","author":"Liu","year":"1999","journal-title":"Analytical Biochemistry"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1021\/acsinfecdis.8b00336","article-title":"Structural adaptation of darunavir analogues against primary mutations in HIV-1 protease","volume":"5","author":"Lockbaum","year":"2019","journal-title":"ACS Infectious Diseases"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"4786","DOI":"10.1021\/bi200033z","article-title":"The L76V drug resistance mutation decreases the dimer stability and rate of autoprocessing of HIV-1 protease by reducing internal hydrophobic contacts","volume":"50","author":"Louis","year":"2011","journal-title":"Biochemistry"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1002\/prot.10140","article-title":"Combining mutations in HIV-1 protease to understand mechanisms of resistance","volume":"48","author":"Mahalingam","year":"2002","journal-title":"Proteins"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1126\/science.2106161","article-title":"Novel fluorogenic substrates for assaying retroviral proteases by resonance energy transfer","volume":"247","author":"Matayoshi","year":"1990","journal-title":"Science"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"3238","DOI":"10.1021\/acs.chemrev.0c00648","article-title":"Drug design strategies to avoid resistance in direct-acting antivirals and beyond","volume":"121","author":"Matthew","year":"2021","journal-title":"Chemical Reviews"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1016\/j.bmcl.2003.12.008","article-title":"Novel arylsulfonamides possessing sub-picomolar HIV protease activities and potent anti-HIV activity against wild-type and drug-resistant viral strains","volume":"14","author":"Miller","year":"2004","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"3496","DOI":"10.1016\/j.bmcl.2005.05.129","article-title":"Novel P1 chain-extended HIV protease inhibitors possessing potent anti-HIV activity and remarkable inverse antiviral resistance profiles","volume":"15","author":"Miller","year":"2005","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1016\/j.bmcl.2006.01.035","article-title":"Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: the discovery of GW0385","volume":"16","author":"Miller","year":"2006","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"4176","DOI":"10.1128\/JVI.03486-12","article-title":"Structural and thermodynamic basis of amprenavir\/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50","volume":"87","author":"Mittal","year":"2013","journal-title":"Journal of Virology"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1021\/bi027019u","article-title":"A major role for A set of non-active site mutations in the development of HIV-1 protease drug resistance","volume":"42","author":"Muzammil","year":"2003","journal-title":"Biochemistry"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.chembiol.2013.07.014","article-title":"Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance","volume":"20","author":"Nalam","year":"2013","journal-title":"Chemistry & Biology"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"7887","DOI":"10.1021\/ja060682b","article-title":"Computational simulations of HIV-1 proteasesmulti-drug resistance due to nonactive site mutation L90M","volume":"128","author":"Ode","year":"2006","journal-title":"Journal of the American Chemical Society"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1016\/j.jmb.2011.03.053","article-title":"Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope","volume":"410","author":"\u00d6zen","year":"2011","journal-title":"Journal of Molecular Biology"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1021\/ct200668a","article-title":"Hiv-1 protease and substrate coevolution validates the substrate envelope as the substrate recognition pattern","volume":"8","author":"\u00d6zen","year":"2012","journal-title":"Journal of Chemical Theory and Computation"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"15993","DOI":"10.1073\/pnas.1414063111","article-title":"Structural basis and distal effects of gag substrate coevolution in drug resistance to HIV-1 protease","volume":"111","author":"\u00d6zen","year":"2014","journal-title":"PNAS"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"e417","DOI":"10.1016\/S2352-3018(15)00176-9","article-title":"Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial","volume":"2","author":"Paton","year":"2015","journal-title":"The Lancet. HIV"},{"key":"bib58","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1177\/135965350801300214","article-title":"Virological response to darunavir\/ritonavir-based regimens in antiretroviral-experienced patients (PREDIZISTA study)","volume":"13","author":"Pellegrin","year":"2008","journal-title":"Antiviral Therapy"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"12446","DOI":"10.1128\/JVI.78.22.12446-12454.2004","article-title":"Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease","volume":"78","author":"Prabu-Jeyabalan","year":"2004","journal-title":"Journal of Virology"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"11956","DOI":"10.1021\/ja504096m","article-title":"Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease","volume":"136","author":"Ragland","year":"2014","journal-title":"Journal of the American Chemical Society"},{"key":"bib61","doi-asserted-by":"publisher","first-page":"5671","DOI":"10.1021\/acs.jctc.7b00601","article-title":"Elucidating the interdependence of drug resistance from combinations of mutations","volume":"13","author":"Ragland","year":"2017","journal-title":"Journal of Chemical Theory and Computation"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1093\/nar\/gkg100","article-title":"Human immunodeficiency virus reverse transcriptase and protease sequence database","volume":"31","author":"Rhee","year":"2003","journal-title":"Nucleic Acids Research"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/0014-5793(89)81251-7","article-title":"Effective blocking of HIV-1 proteinase activity by characteristic inhibitors of aspartic proteinases","volume":"247","author":"Richards","year":"1989","journal-title":"FEBS Letters"},{"key":"bib64","doi-asserted-by":"crossref","first-page":"11939","DOI":"10.1016\/S0021-9258(19)50290-3","article-title":"Regulation of autoproteolysis of the HIV-1 and HIV-2 proteases with engineered amino acid substitutions","volume":"268","author":"Ros\u00e9","year":"1993","journal-title":"The Journal of Biological Chemistry"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"8062","DOI":"10.1021\/acs.jmedchem.9b00838","article-title":"Hiv-1 protease inhibitors incorporating stereochemically defined P2\u2019 ligands to optimize hydrogen bonding in the substrate envelope","volume":"62","author":"Rusere","year":"2019","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"6612","DOI":"10.1073\/pnas.85.18.6612","article-title":"Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin a","volume":"85","author":"Seelmeier","year":"1988","journal-title":"PNAS"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"3699","DOI":"10.1111\/j.1742-4658.2010.07771.x","article-title":"Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters","volume":"277","author":"Shen","year":"2010","journal-title":"The FEBS Journal"},{"key":"bib68","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24183243","article-title":"Reviewing HIV-1 gag mutations in protease inhibitors resistance: insights for possible novel gag inhibitor designs","volume":"24","author":"Su","year":"2019","journal-title":"Molecules"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1021\/jm049560p","article-title":"Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor","volume":"48","author":"Surleraux","year":"2005","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"759","DOI":"10.2147\/tcrm.s1709","article-title":"Combating HIV resistance-focus on darunavir","volume":"4","author":"Tremblay","year":"2008","journal-title":"Therapeutics and Clinical Risk Management"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1093\/jac\/dkr504","article-title":"Long-Term efficacy of darunavir\/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study","volume":"67","author":"Valantin","year":"2012","journal-title":"The Journal of Antimicrobial Chemotherapy"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1080\/23744235.2019.1694696","article-title":"Lack of impact of protease inhibitor resistance-associated mutations on the outcome of HIV-1-infected patients switching to darunavir-based dual therapy","volume":"52","author":"Vizcarra","year":"2020","journal-title":"Infectious Diseases"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1128\/AAC.47.2.759-769.2003","article-title":"Selection of high-level resistance to human immunodeficiency virus type 1 protease inhibitors","volume":"47","author":"Watkins","year":"2003","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.antiviral.2009.10.003","article-title":"Fifteen years of HIV protease inhibitors: raising the barrier to resistance","volume":"85","author":"Wensing","year":"2010","journal-title":"Antiviral Research"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1021\/acs.jctc.9b00781","article-title":"Characterizing protein-ligand binding using atomistic simulation and machine learning: application to drug resistance in HIV-1 protease","volume":"16","author":"Whitfield","year":"2020","journal-title":"Journal of Chemical Theory and Computation"},{"key":"bib76","doi-asserted-by":"publisher","DOI":"10.1038\/srep11286","article-title":"Fluorogenic assay for inhibitors of HIV-1 protease with sub-picomolar affinity","volume":"5","author":"Windsor","year":"2015","journal-title":"Scientific Reports"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"8540","DOI":"10.1128\/JVI.00522-15","article-title":"Primer ID validates template sampling depth and greatly reduces the error rate of next-generation sequencing of HIV-1 genomic RNA populations","volume":"89","author":"Zhou","year":"2015","journal-title":"Journal of Virology"},{"key":"bib78","article-title":"Primer ID template consensus sequence (TCS) pipeline","volume-title":"Github","author":"Zhou","year":"2019","unstructured":"Zhou S. 2019. Primer ID template consensus sequence (TCS) pipeline. Github. 1.33. https:\/\/github.com\/SwanstromLab\/PID."},{"key":"bib79","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1021\/acsmedchemlett.0c00043","article-title":"Novel HIV-1 protease inhibitors with morpholine as the P2 ligand to enhance activity against DRV-resistant variants","volume":"11","author":"Zhu","year":"2020","journal-title":"ACS Medicinal Chemistry Letters"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/80328\/elife-80328-v3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/80328\/elife-80328-v3.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/80328","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:05:28Z","timestamp":1697058328000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/80328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,15]]},"references-count":79,"alternative-id":["10.7554\/eLife.80328"],"URL":"https:\/\/doi.org\/10.7554\/elife.80328","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/837120","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/837120","asserted-by":"object"}],"is-supplemented-by":[{"id-type":"doi","id":"10.17615\/rb7r-tx62","asserted-by":"subject"},{"id-type":"doi","id":"10.17615\/3697-3v58","asserted-by":"subject"},{"id-type":"accession","id":"PRJNA853351","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.80328.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.80328.sa0","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.80328.sa1","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,15]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"e80328"}}