{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:12:35Z","timestamp":1772172755232,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008363","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T00:00:00Z","timestamp":1631836800000}}],"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T00:00:00Z","timestamp":1630972800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["179 571"],"award-info":[{"award-number":["179 571"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["148522"],"award-info":[{"award-number":["148522"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SHCS Research Foundation"},{"name":"Stiftung Yvonne Jacob"},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["AI136618"],"award-info":[{"award-number":["AI136618"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Although combination antiretroviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Most of this knowledge is derived from studies of subtype B genotypes, despite not being the most abundant subtype worldwide. Here, we present a methodology for the comparison of mutational networks in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational networks from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models for a larger number of resistance mutations and develop a statistical test to assess differences in the inferred mutational networks between two groups. We apply this method to infer the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional cohort of HIV-1 subtype C genotypes from South Africa, as well as to a data set of subtype B genotypes obtained from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. The inferred mutational networks for subtype B versus C are significantly different sharing only five constraints on the order of accumulating mutations with mutation at residue 54 as the parental event. The results also suggest that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational networks between any two groups.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008363","type":"journal-article","created":{"date-parts":[[2021,9,7]],"date-time":"2021-09-07T14:01:24Z","timestamp":1631023284000},"page":"e1008363","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7459-8186","authenticated-orcid":true,"given":"Susana","family":"Posada-C\u00e9spedes","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3021-5101","authenticated-orcid":true,"given":"Gert","family":"Van Zyl","sequence":"additional","affiliation":[]},{"given":"Hesam","family":"Montazeri","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5357-2705","authenticated-orcid":true,"given":"Jack","family":"Kuipers","sequence":"additional","affiliation":[]},{"given":"Soo-Yon","family":"Rhee","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9220-8348","authenticated-orcid":true,"given":"Roger","family":"Kouyos","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1142-6723","authenticated-orcid":true,"given":"Huldrych F.","family":"G\u00fcnthard","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0573-6119","authenticated-orcid":true,"given":"Niko","family":"Beerenwinkel","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,9,7]]},"reference":[{"issue":"4","key":"pcbi.1008363.ref001","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1001\/jama.2018.8431","article-title":"Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel","volume":"320","author":"MS Saag","year":"2018","journal-title":"JAMA"},{"issue":"1","key":"pcbi.1008363.ref002","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3851\/IMP2437","article-title":"Rates of emergence of HIV drug resistance in resource-limited settings: a systematic review","volume":"18","author":"KM Stadeli","year":"2013","journal-title":"Antivir Ther"},{"issue":"2","key":"pcbi.1008363.ref003","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/cid\/ciy463","article-title":"Human Immunodeficiency Virus drug resistance: 2018 recommendations of the International Antiviral Society-USA Panel","volume":"68","author":"HF G\u00fcnthard","year":"2019","journal-title":"Clin Infect Dis"},{"issue":"9","key":"pcbi.1008363.ref004","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1086\/598503","article-title":"Are all subtypes created equal? The effectiveness of antiretroviral therapy against non-subtype B HIV-1","volume":"48","author":"SL Kosakovsky Pond","year":"2009","journal-title":"Clin Infect Dis"},{"issue":"3","key":"pcbi.1008363.ref005","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1097\/00126334-200307010-00007","article-title":"Patterns of point mutations associated with antiretroviral drug treatment failure in CRF01_AE (subtype E) infection differ from subtype B infection","volume":"33","author":"K Ariyoshi","year":"2003","journal-title":"J Acquir Immune Defic Syndr"},{"key":"pcbi.1008363.ref006","doi-asserted-by":"crossref","first-page":"S63","DOI":"10.1097\/00002030-200406003-00012","article-title":"HIV-1 subtype distribution and the problem of drug resistance","volume":"18","author":"MA Wainberg","year":"2004","journal-title":"AIDS"},{"issue":"4","key":"pcbi.1008363.ref007","doi-asserted-by":"crossref","first-page":"e112","DOI":"10.1371\/journal.pmed.0020112","article-title":"Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration","volume":"2","author":"R Kantor","year":"2005","journal-title":"PLoS Med"},{"key":"pcbi.1008363.ref008","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1097\/QCO.0b013e3280109122","article-title":"Impact of HIV-1 pol diversity on drug resistance and its clinical implications","volume":"19","author":"R Kantor","year":"2006","journal-title":"Curr Opin Infect Dis"},{"issue":"11","key":"pcbi.1008363.ref009","article-title":"Differences in resistance mutations among HIV-1 non-subtype B infections: a systematic review of evidence (1996-2008)","volume":"12","author":"JL Martinez-Cajas","year":"2009","journal-title":"J Int AIDS Soc"},{"key":"pcbi.1008363.ref010","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.meegid.2016.06.047","article-title":"Differences among HIV-1 subtypes in drug resistance against integrase inhibitors","volume":"46","author":"YS Han","year":"2016","journal-title":"Infect Genet Evol"},{"key":"pcbi.1008363.ref011","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.molmed.2011.12.001","article-title":"The origin and diversity of the HIV-1 pandemic","volume":"18","author":"J Hemelaar","year":"2012","journal-title":"Trends Mol Med"},{"issue":"2","key":"pcbi.1008363.ref012","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S1473-3099(18)30647-9","article-title":"Global and regional molecular epidemiology of HIV-1, 1990\u20132015: a systematic review, global survey, and trend analysis","volume":"19","author":"J Hemelaar","year":"2019","journal-title":"Lancet Infect Dis"},{"issue":"4934","key":"pcbi.1008363.ref013","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1126\/science.2479983","article-title":"Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT)","volume":"246","author":"BA Larder","year":"1989","journal-title":"Science"},{"issue":"1","key":"pcbi.1008363.ref014","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/infdis\/165.1.105","article-title":"Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency Virus-positive subjects","volume":"165","author":"CAB Boucher","year":"1992","journal-title":"J Infect Dis"},{"key":"pcbi.1008363.ref015","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/374569a0","article-title":"In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors","volume":"374","author":"J Condra","year":"1995","journal-title":"Nature"},{"key":"pcbi.1008363.ref016","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1038\/nm0796-760","article-title":"Ordered accumulation of mutations in HIV protease confers resistance to ritonavir","volume":"2","author":"A Molla","year":"1996","journal-title":"Nat Med"},{"issue":"464","key":"pcbi.1008363.ref017","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1198\/016214503000000792","article-title":"Characterizing the progression of viral mutations over time","volume":"98","author":"AS Foulkes","year":"2003","journal-title":"J Am Stat Assoc"},{"issue":"1","key":"pcbi.1008363.ref018","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/biostatistics\/kxj033","article-title":"A mutagenetic tree hidden Markov model for longitudinal clonal HIV sequence data","volume":"8","author":"N Beerenwinkel","year":"2006","journal-title":"Biostatistics"},{"issue":"19","key":"pcbi.1008363.ref019","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/btp466","article-title":"A phylogenetic and Markov model approach for the reconstruction of mutational pathways of drug resistance","volume":"25","author":"P Buendia","year":"2009","journal-title":"Bioinformatics"},{"issue":"12","key":"pcbi.1008363.ref020","first-page":"3323","article-title":"Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study","volume":"70","author":"WL Yang","year":"2015","journal-title":"J Antimicrob Chemoth"},{"issue":"24","key":"pcbi.1008363.ref021","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1093\/bioinformatics\/btl508","article-title":"Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance","volume":"22","author":"K Deforche","year":"2006","journal-title":"Bioinformatics"},{"issue":"16","key":"pcbi.1008363.ref022","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1097\/QAD.0b013e32830fe940","article-title":"Bayesian network analyses of resistance pathways against efavirenz and nevirapine","volume":"22","author":"K Deforche","year":"2008","journal-title":"AIDS"},{"issue":"18","key":"pcbi.1008363.ref023","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1093\/bioinformatics\/btz076","article-title":"Gag-protease coevolution shapes the outcome of lopinavir-inclusive treatment regimens in chronically infected HIV-1 subtype C patients","volume":"35","author":"V Marie","year":"2019","journal-title":"Bioinformatics"},{"issue":"26","key":"pcbi.1008363.ref024","article-title":"HIV-1 mutational pathways under multidrug therapy","volume":"8","author":"G Lawyer","year":"2011","journal-title":"AIDS Res Ther"},{"issue":"6","key":"pcbi.1008363.ref025","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1089\/cmb.2005.12.584","article-title":"Learning multiple evolutionary pathways from cross-sectional data","volume":"12","author":"N Beerenwinkel","year":"2005","journal-title":"J Comput Biol"},{"issue":"11","key":"pcbi.1008363.ref026","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1086\/430005","article-title":"Estimating HIV evolutionary pathways and the genetic barrier to drug resistance","volume":"191","author":"N Beerenwinkel","year":"2005","journal-title":"J Infect Dis"},{"issue":"4","key":"pcbi.1008363.ref027","doi-asserted-by":"crossref","first-page":"893","DOI":"10.3150\/07-BEJ6133","article-title":"Conjuctive Bayesian networks","volume":"13","author":"N Beerenwinkel","year":"2007","journal-title":"Bernoulli"},{"issue":"3","key":"pcbi.1008363.ref028","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1093\/biomet\/asp023","article-title":"Markov models for accumulating mutations","volume":"96","author":"N Beerenwinkel","year":"2009","journal-title":"Biometrika"},{"issue":"18","key":"pcbi.1008363.ref029","doi-asserted-by":"crossref","first-page":"3016","DOI":"10.1093\/bioinformatics\/btv296","article-title":"CAPRI: efficient inference of cancer progression models from cross-sectional data","volume":"31","author":"D Ramazzotti","year":"2015","journal-title":"Bioinformatics"},{"key":"pcbi.1008363.ref030","doi-asserted-by":"crossref","first-page":"1176934318785167","DOI":"10.1177\/1176934318785167","article-title":"Modeling cumulative biological phenomena with suppes-Bayes causal networks","volume":"14","author":"D Ramazzotti","year":"2018","journal-title":"Evolutionary Bioinformatics"},{"issue":"21","key":"pcbi.1008363.ref031","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1093\/bioinformatics\/btp505","article-title":"Quantifying cancer progression with conjunctive Bayesian networks","volume":"25","author":"M Gerstung","year":"2009","journal-title":"Bioinformatics"},{"issue":"5","key":"pcbi.1008363.ref032","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1002\/bimj.201100186","article-title":"Cumulative disease progression models for cross-sectional data: A review and comparison","volume":"54","author":"K Hainke","year":"2012","journal-title":"Biom J"},{"issue":"5","key":"pcbi.1008363.ref033","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1093\/bioinformatics\/btx663","article-title":"Cancer progression models and fitness landscapes: a many-to-many relationship","volume":"34","author":"R Diaz-Uriarte","year":"2017","journal-title":"Bioinformatics"},{"issue":"8","key":"pcbi.1008363.ref034","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1007246","article-title":"Every which way? On predicting tumor evolution using cancer progression models","volume":"15","author":"R Diaz-Uriarte","year":"2019","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1008363.ref035","doi-asserted-by":"crossref","first-page":"i727","DOI":"10.1093\/bioinformatics\/btw459","article-title":"Large-scale inference of conjunctive Bayesian networks","volume":"32","author":"M Montazeri","year":"2016","journal-title":"Bioinformatics"},{"issue":"4","key":"pcbi.1008363.ref036","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1093\/jac\/dkr569","article-title":"Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir\/ritonavir as their first protease inhibitor","volume":"67","author":"TJ Barber","year":"2012","journal-title":"J Antimicrob Chemother"},{"key":"pcbi.1008363.ref037","doi-asserted-by":"crossref","first-page":"e86239","DOI":"10.1371\/journal.pone.0086239","article-title":"Comparable long-term efficacy of Lopinavir\/Ritonavir and similar drug-resistance profiles in different HIV-1 subtypes","volume":"1","author":"Z Grossman","year":"2014","journal-title":"PLoS One"},{"issue":"11","key":"pcbi.1008363.ref038","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0895-7177(93)90204-C","article-title":"Simulated annealing: practice versus theory","volume":"18","author":"L Ingber","year":"1993","journal-title":"Mathl Comput Modelling"},{"issue":"4598","key":"pcbi.1008363.ref039","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1126\/science.220.4598.671","article-title":"Optimization by simulated annealing","volume":"220","author":"S Kirkpatrick","year":"1983","journal-title":"Science"},{"issue":"1","key":"pcbi.1008363.ref040","first-page":"33","article-title":"Adaptive simulated annealing (ASA): lessons learned","volume":"25","author":"L Ingber","year":"1996","journal-title":"Control and Cybernetics"},{"issue":"1","key":"pcbi.1008363.ref041","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0165-1684(99)00084-5","article-title":"Adaptive simulated annealing for optimization in signal processing applications","volume":"79","author":"S Chen","year":"1999","journal-title":"Signal Processing"},{"issue":"13","key":"pcbi.1008363.ref042","doi-asserted-by":"crossref","first-page":"i519","DOI":"10.1093\/bioinformatics\/bty240","article-title":"Improved pathway reconstruction from RNA interference screens by exploiting off-target effects","volume":"34","author":"S Srivatsa","year":"2018","journal-title":"Bioinformatics"},{"issue":"520","key":"pcbi.1008363.ref043","article-title":"The effect of sequencing errors on metagenomic gene prediction","volume":"10","author":"KJ Hoff","year":"2009","journal-title":"BMC Genomics"},{"issue":"1","key":"pcbi.1008363.ref044","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/nar\/gkg100","article-title":"Human immunodeficiency virus reverse transcriptase and protease sequence database","volume":"31","author":"SY Rhee","year":"2003","journal-title":"Nucleic Acids Res"},{"issue":"Suppl 1","key":"pcbi.1008363.ref045","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1086\/505356","article-title":"Rationale and uses of a public HIV drug-resistance database","volume":"194","author":"RW Shafer","year":"2006","journal-title":"J Infect Dis"},{"issue":"16","key":"pcbi.1008363.ref046","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1001\/archinte.167.16.1782","article-title":"Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: a comparison of different regimen types","volume":"167","author":"V von Wyl","year":"2007","journal-title":"Arch Intern Med"},{"issue":"5","key":"pcbi.1008363.ref047","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1093\/ije\/dyp321","article-title":"Cohort profile: the Swiss HIV Cohort study","volume":"39","author":"Swiss HIV Cohort Study","year":"2010","journal-title":"Int J Epidemiol"},{"key":"pcbi.1008363.ref048","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1002\/jmv.21315","article-title":"Natural polymorphisms in HIV-1 protease: impact on effectiveness of a first-line lopinavir-containing antiretroviral therapy regimen","volume":"80","author":"K Champenois","year":"2008","journal-title":"J Med Virol"},{"issue":"17","key":"pcbi.1008363.ref049","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1097\/00002030-199912030-00006","article-title":"Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy","volume":"13","author":"M Nijhuis","year":"1999","journal-title":"AIDS"},{"issue":"11","key":"pcbi.1008363.ref050","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1097\/00002030-200007280-00004","article-title":"Protease sequences from HIV-1 group M subtypes A\u2013H reveal distinct amino acid mutation patterns associated with protease resistance in protease inhibitor-naive individuals worldwide","volume":"14","author":"D Pieniazek","year":"2000","journal-title":"AIDS"},{"issue":"11","key":"pcbi.1008363.ref051","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1128\/JCM.38.11.3919-3925.2000","article-title":"Genetic diversity of protease and reverse transcriptase sequences in non-subtype-B human immunodeficiency virus type 1 strains: evidence of many minor drug resistance mutations in treatment-naive patients","volume":"38","author":"L Vergne","year":"2000","journal-title":"J Clin Microbiol"},{"issue":"2","key":"pcbi.1008363.ref052","first-page":"67","article-title":"HIV-1 drug resistance mutations: an updated framework for the second decade of HAART","volume":"10","author":"RW Shafer","year":"2008","journal-title":"AIDS rev"},{"issue":"7","key":"pcbi.1008363.ref053","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1097\/00002030-200305020-00003","article-title":"Improving lopinavir genotype algorithm through phenotype correlations: novel mutation patterns and amprenavir cross-resistance","volume":"17","author":"NT Parkin","year":"2003","journal-title":"AIDS"},{"issue":"1","key":"pcbi.1008363.ref054","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1086\/380509","article-title":"Incidence of resistance in a double-blind study comparing lopinavir\/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine","volume":"189","author":"DJ Kempf","year":"2004","journal-title":"J Infect Dis"},{"issue":"1","key":"pcbi.1008363.ref055","first-page":"4","article-title":"Ritonavir-boosted protease inhibitor monotherapy for the treatment of HIV-1 infection","volume":"10","author":"S Sahali","year":"2008","journal-title":"AIDS Rev"},{"issue":"11","key":"pcbi.1008363.ref056","doi-asserted-by":"crossref","first-page":"e50307","DOI":"10.1371\/journal.pone.0050307","article-title":"Long-lasting protection of activity of nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) by boosted PI containing regimens","volume":"7","author":"AU Scherrer","year":"2012","journal-title":"PLoS One"},{"issue":"9","key":"pcbi.1008363.ref057","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1038\/nm.2892","article-title":"Antiretroviral dynamics determines HIV evolution and predicts therapy outcome","volume":"18","author":"DI Rosenbloom","year":"2012","journal-title":"Nat Med"},{"issue":"10","key":"pcbi.1008363.ref058","doi-asserted-by":"crossref","first-page":"e77691","DOI":"10.1371\/journal.pone.0077691","article-title":"Adherence as a predictor of the development of class-specific resistance mutations: the Swiss HIV Cohort Study","volume":"8","author":"V von Wyl","year":"2013","journal-title":"PLoS One"},{"issue":"5","key":"pcbi.1008363.ref059","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1097\/QAD.0b013e328336784d","article-title":"The evolution of protease mutation 76V is associated with protease mutation 46I and gag mutation 431V","volume":"24","author":"E Knops","year":"2010","journal-title":"AIDS"},{"issue":"9","key":"pcbi.1008363.ref060","doi-asserted-by":"crossref","first-page":"3848","DOI":"10.1172\/JCI67399","article-title":"Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance","volume":"123","author":"SA Rabi","year":"2013","journal-title":"J Clin Invest"},{"issue":"2","key":"pcbi.1008363.ref061","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1097\/COH.0000000000000344","article-title":"Future technologies for monitoring HIV drug resistance and cure","volume":"12","author":"UM Parikh","year":"2017","journal-title":"Curr Opin HIV AIDS"},{"issue":"214","key":"pcbi.1008363.ref062","article-title":"Increased acquired protease inhibitor drug resistance mutations in minor HIV-1 quasispecies from infected patients suspected of failing on national second-line therapy in South Africa","volume":"21","author":"AE Obasa","year":"2021","journal-title":"BMC Infect Dis"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1008363","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T00:00:00Z","timestamp":1631836800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008363","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T13:40:57Z","timestamp":1631886057000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008363"}},"subtitle":[],"editor":[{"given":"Sergei L.","family":"Kosakovsky Pond","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2021,9,7]]},"references-count":62,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1008363","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.09.25.312942","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,7]]}}}