{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T19:22:59Z","timestamp":1749410579239},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Retrovirology"],"published-print":{"date-parts":[[2008,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Combination anti-viral therapies have reduced treatment failure rates by requiring multiple specific mutations to be selected on the same viral genome to impart high-level drug resistance. To determine if the common protease inhibitor resistance mutation L90M is only selected once or repeatedly on different HIV genetic backbones during the course of failed anti-viral therapies we analyzed a linked region of the viral genome during the evolution of multi-drug resistance.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Using L90M allele specific PCR we amplified and sequenced gag-pro regions linked to very early L90M containing HIV variants prior to their emergence and detection as dominant viruses in 15 failed salvage therapy patients. The early minority L90M linked sequences were then compared to those of the later L90M viruses that came to dominate the plasma quasispecies. Using Bayesian evolutionary analysis sampling trees the emergence of L90M containing viruses was seen to take place on multiple occasion in 5 patients, only once for 2 patients and an undetermined number of time for the remaining 8 patients.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These results indicate that early L90M mutants can frequently be displaced by viruses carrying independently selected L90M mutations rather than by descendents of the earlier mutants.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1742-4690-5-7","type":"journal-article","created":{"date-parts":[[2008,1,25]],"date-time":"2008-01-25T19:20:46Z","timestamp":1201288846000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Multiple independent origins of a protease inhibitor resistance mutation in salvage therapy patients"],"prefix":"10.1186","volume":"5","author":[{"given":"Amit","family":"Kapoor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beth","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W","family":"Shafer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Shulman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soo-Yon","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric L","family":"Delwart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2008,1,25]]},"reference":[{"key":"832_CR1","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1126\/science.7824947","volume":"267","author":"JM Coffin","year":"1995","unstructured":"Coffin JM: HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995, 267: 483-489. 10.1126\/science.7824947.","journal-title":"Science"},{"key":"832_CR2","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1002\/jmv.2022","volume":"65","author":"S Paolucci","year":"2001","unstructured":"Paolucci S, Baldanti F, Campanini G, Zavattoni M, Cattaneo E, Dossena L, Gerna G: Analysis of HIV drug-resistant quasispecies in plasma, peripheral blood mononuclear cells and viral isolates from treatment-naive and HAART patients. J Med Virol. 2001, 65: 207-217. 10.1002\/jmv.2022.","journal-title":"J Med Virol"},{"key":"832_CR3","doi-asserted-by":"publisher","first-page":"11514","DOI":"10.1073\/pnas.95.20.11514","volume":"95","author":"TB Kepler","year":"1998","unstructured":"Kepler TB, Perelson AS: Drug concentration heterogeneity facilitates the evolution of drug resistance. Proc Natl Acad Sci USA. 1998, 95: 11514-11519. 10.1073\/pnas.95.20.11514.","journal-title":"Proc Natl Acad Sci USA"},{"key":"832_CR4","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1128\/JVI.78.5.2434-2444.2004","volume":"78","author":"M Magierowska","year":"2004","unstructured":"Magierowska M, Bernardin F, Garg S, Staprans S, Miller MD, Van Rompay KK, Delwart EL: Highly uneven distribution of tenofovir-selected simian immunodeficiency virus in different anatomical sites of rhesus macaques. J Virol. 2004, 78: 2434-2444. 10.1128\/JVI.78.5.2434-2444.2004.","journal-title":"J Virol"},{"key":"832_CR5","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/nm0796-760","volume":"2","author":"A Molla","year":"1996","unstructured":"Molla A, Korneyeva M, Gao Q, Vasavanonda S, Schipper PJ, Mo HM, Markowitz M, Chernyavskiy T, Niu P, Lyons N, et al: Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med. 1996, 2: 760-766. 10.1038\/nm0796-760.","journal-title":"Nat Med"},{"key":"832_CR6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1128\/CMR.15.2.247-277.2002","volume":"15","author":"RW Shafer","year":"2002","unstructured":"Shafer RW: Genotypic testing for human immunodeficiency virus type 1 drug resistance. Clin Microbiol Rev. 2002, 15: 247-277. 10.1128\/CMR.15.2.247-277.2002.","journal-title":"Clin Microbiol Rev"},{"key":"832_CR7","doi-asserted-by":"crossref","first-page":"8270","DOI":"10.1128\/jvi.70.12.8270-8276.1996","volume":"70","author":"JH Condra","year":"1996","unstructured":"Condra JH, Holder DJ, Schleif WA, Blahy OM, Danovich RM, Gabryelski LJ, Graham DJ, Laird D, Quintero JC, Rhodes A, et al: Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J Virol. 1996, 70: 8270-8276.","journal-title":"J Virol"},{"key":"832_CR8","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/374569a0","volume":"374","author":"JH Condra","year":"1995","unstructured":"Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al: In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors [see comments]. Nature. 1995, 374: 569-571. 10.1038\/374569a0.","journal-title":"Nature"},{"key":"832_CR9","doi-asserted-by":"publisher","first-page":"7000","DOI":"10.1128\/JVI.76.14.7000-7009.2002","volume":"76","author":"GH Kijak","year":"2002","unstructured":"Kijak GH, Simon V, Balfe P, Vanderhoeven J, Pampuro SE, Zala C, Ochoa C, Cahn P, Markowitz M, Salomon H: Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure. J Virol. 2002, 76: 7000-7009. 10.1128\/JVI.76.14.7000-7009.2002.","journal-title":"J Virol"},{"key":"832_CR10","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1097\/00002030-199912030-00006","volume":"13","author":"M Nijhuis","year":"1999","unstructured":"Nijhuis M, Schuurman R, de Jong D, Erickson J, Gustchina E, Albert J, Schipper P, Gulnik S, Boucher CA: Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. Aids. 1999, 13: 2349-2359. 10.1097\/00002030-199912030-00006.","journal-title":"Aids"},{"key":"832_CR11","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.1128\/JVI.72.9.7632-7637.1998","volume":"72","author":"F Mammano","year":"1998","unstructured":"Mammano F, Petit C, Clavel F: Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol. 1998, 72: 7632-7637.","journal-title":"J Virol"},{"key":"832_CR12","doi-asserted-by":"publisher","first-page":"5952","DOI":"10.1074\/jbc.M108005200","volume":"277","author":"H Gatanaga","year":"2002","unstructured":"Gatanaga H, Suzuki Y, Tsang H, Yoshimura K, Kavlick MF, Nagashima K, Gorelick RJ, Mardy S, Tang C, Summers MF, Mitsuya H: Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors. J Biol Chem. 2002, 277: 5952-5961. 10.1074\/jbc.M108005200.","journal-title":"J Biol Chem"},{"key":"832_CR13","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1128\/JVI.75.2.589-594.2001","volume":"75","author":"HC Cote","year":"2001","unstructured":"Cote HC, Brumme ZL, Harrigan PR: Human immunodeficiency virus type 1 protease cleavage site mutations associated with protease inhibitor cross-resistance selected by indinavir, ritonavir, and\/or saquinavir. J Virol. 2001, 75: 589-594. 10.1128\/JVI.75.2.589-594.2001.","journal-title":"J Virol"},{"key":"832_CR14","doi-asserted-by":"publisher","first-page":"14441","DOI":"10.1073\/pnas.95.24.14441","volume":"95","author":"M Nijhuis","year":"1998","unstructured":"Nijhuis M, Boucher CA, Schipper P, Leitner T, Schuurman R, Albert J: Stochastic processes strongly influence HIV-1 evolution during suboptimal protease-inhibitor therapy. Proc Natl Acad Sci USA. 1998, 95: 14441-14446. 10.1073\/pnas.95.24.14441.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"Suppl 3","key":"832_CR15","first-page":"S75","volume":"10","author":"JM Coffin","year":"1996","unstructured":"Coffin JM: HIV viral dynamics. Aids. 1996, 10 (Suppl 3): S75-84.","journal-title":"Aids"},{"key":"832_CR16","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1006\/viro.1996.0266","volume":"219","author":"KA Barrie","year":"1996","unstructured":"Barrie KA, Perez EE, Lamers SL, Farmerie WG, Dunn BM, Sleasman JW, Goodenow MM: Natural variation in HIV-1 protease, Gag p7 and p6, and protease cleavage sites within gag\/pol polyproteins: amino acid substitutions in the absence of protease inhibitors in mothers and children infected by human immunodeficiency virus type 1. Virology. 1996, 219: 407-416. 10.1006\/viro.1996.0266.","journal-title":"Virology"},{"key":"832_CR17","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1128\/jvi.71.2.1089-1096.1997","volume":"71","author":"G Croteau","year":"1997","unstructured":"Croteau G, Doyon L, Thibeault D, McKercher G, Pilote L, Lamarre D: Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol. 1997, 71: 1089-1096.","journal-title":"J Virol"},{"key":"832_CR18","doi-asserted-by":"publisher","first-page":"11104","DOI":"10.1128\/JVI.76.21.11104-11112.2002","volume":"76","author":"JD Barbour","year":"2002","unstructured":"Barbour JD, Wrin T, Grant RM, Martin JN, Segal MR, Petropoulos CJ, Deeks SG: Evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults. J Virol. 2002, 76: 11104-11112. 10.1128\/JVI.76.21.11104-11112.2002.","journal-title":"J Virol"},{"issue":"Pt 3","key":"832_CR19","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1099\/0022-1317-77-3-419","volume":"77","author":"AM Borman","year":"1996","unstructured":"Borman AM, Paulous S, Clavel F: Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug. J Gen Virol. 1996, 77 (Pt 3): 419-426.","journal-title":"J Gen Virol"},{"key":"832_CR20","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/374569a0","volume":"374","author":"JH Condra","year":"1995","unstructured":"Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al: In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995, 374: 569-571. 10.1038\/374569a0.","journal-title":"Nature"},{"key":"832_CR21","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1056\/NEJM200102153440702","volume":"344","author":"SG Deeks","year":"2001","unstructured":"Deeks SG, Wrin T, Liegler T, Hoh R, Hayden M, Barbour JD, Hellmann NS, Petropoulos CJ, McCune JM, Hellerstein MK, Grant RM: Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med. 2001, 344: 472-480. 10.1056\/NEJM200102153440702.","journal-title":"N Engl J Med"},{"key":"832_CR22","doi-asserted-by":"publisher","first-page":"6729","DOI":"10.1128\/JVI.75.14.6729-6736.2001","volume":"75","author":"L Doukhan","year":"2001","unstructured":"Doukhan L, Delwart E: Population genetic analysis of the protease locus of human immunodeficiency virus type 1 quasispecies undergoing drug selection, using a denaturing gradient-heteroduplex tracking assay. J Virol. 2001, 75: 6729-6736. 10.1128\/JVI.75.14.6729-6736.2001.","journal-title":"J Virol"},{"key":"832_CR23","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1086\/379773","volume":"37","author":"RT Gandhi","year":"2003","unstructured":"Gandhi RT, Wurcel A, Rosenberg ES, Johnston MN, Hellmann N, Bates M, Hirsch MS, Walker BD: Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus. Clin Infect Dis. 2003, 37: 1693-1698. 10.1086\/379773.","journal-title":"Clin Infect Dis"},{"key":"832_CR24","doi-asserted-by":"publisher","first-page":"4234","DOI":"10.1128\/JVI.78.8.4234-4247.2004","volume":"78","author":"C Charpentier","year":"2004","unstructured":"Charpentier C, Dwyer DE, Mammano F, Lecossier D, Clavel F, Hance AJ: Role of minority populations of human immunodeficiency virus type 1 in the evolution of viral resistance to protease inhibitors. J Virol. 2004, 78: 4234-4247. 10.1128\/JVI.78.8.4234-4247.2004.","journal-title":"J Virol"},{"key":"832_CR25","volume-title":"J Virol","author":"T Nora","year":"2007","unstructured":"Nora T, Charpentier C, Tenaillon O, Hoede C, Clavel F, Hance AJ: Contribution of Recombination to the Evolution of Human Immunodeficiency Viruses Expressing Resistance to Antiretroviral Treatment. J Virol. 2007"},{"key":"832_CR26","doi-asserted-by":"publisher","first-page":"2472","DOI":"10.1128\/JVI.80.5.2472-2482.2006","volume":"80","author":"C Charpentier","year":"2006","unstructured":"Charpentier C, Nora T, Tenaillon O, Clavel F, Hance AJ: Extensive recombination among human immunodeficiency virus type 1 quasispecies makes an important contribution to viral diversity in individual patients. J Virol. 2006, 80: 2472-2482. 10.1128\/JVI.80.5.2472-2482.2006.","journal-title":"J Virol"},{"key":"832_CR27","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1110\/ps.9.10.1898","volume":"9","author":"L Hong","year":"2000","unstructured":"Hong L, Zhang XC, Hartsuck JA, Tang J: Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance. Protein Sci. 2000, 9: 1898-1904.","journal-title":"Protein Sci"},{"key":"832_CR28","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1021\/jp046860+","volume":"109","author":"H Ode","year":"2005","unstructured":"Ode H, Ota M, Neya S, Hata M, Sugiura W, Hoshino T: Resistant mechanism against nelfinavir of human immunodeficiency virus type 1 proteases. J Phys Chem B. 2005, 109: 565-574. 10.1021\/jp046860+.","journal-title":"J Phys Chem B"},{"key":"832_CR29","doi-asserted-by":"publisher","first-page":"7887","DOI":"10.1021\/ja060682b","volume":"128","author":"H Ode","year":"2006","unstructured":"Ode H, Neya S, Hata M, Sugiura W, Hoshino T: Computational simulations of HIV-1 proteases--multi-drug resistance due to nonactive site mutation L90M. J Am Chem Soc. 2006, 128: 7887-7895. 10.1021\/ja060682b.","journal-title":"J Am Chem Soc"},{"key":"832_CR30","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1089\/08892220050116970","volume":"16","author":"F Bally","year":"2000","unstructured":"Bally F, Martinez R, Peters S, Sudre P, Telenti A: Polymorphism of HIV type 1 gag p7\/p1 and p1\/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors. AIDS Res Hum Retroviruses. 2000, 16: 1209-1213. 10.1089\/08892220050116970.","journal-title":"AIDS Res Hum Retroviruses"},{"key":"832_CR31","doi-asserted-by":"publisher","first-page":"2665","DOI":"10.1534\/genetics.105.048975","volume":"172","author":"TC Bruen","year":"2006","unstructured":"Bruen TC, Philippe H, Bryant D: A simple and robust statistical test for detecting the presence of recombination. Genetics. 2006, 172: 2665-2681. 10.1534\/genetics.105.048975.","journal-title":"Genetics"},{"key":"832_CR32","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1093\/molbev\/msj030","volume":"23","author":"DH Huson","year":"2006","unstructured":"Huson DH, Bryant D: Application of phylogenetic networks in evolutionary studies. Mol Biol Evol. 2006, 23: 254-267. 10.1093\/molbev\/msj030.","journal-title":"Mol Biol Evol"},{"key":"832_CR33","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1128\/AAC.47.2.759-769.2003","volume":"47","author":"T Watkins","year":"2003","unstructured":"Watkins T, Resch W, Irlbeck D, Swanstrom R: Selection of high-level resistance to human immunodeficiency virus type 1 protease inhibitors. Antimicrob Agents Chemother. 2003, 47: 759-769. 10.1128\/AAC.47.2.759-769.2003.","journal-title":"Antimicrob Agents Chemother"},{"key":"832_CR34","doi-asserted-by":"publisher","first-page":"4114","DOI":"10.1046\/j.1432-1033.2002.03105.x","volume":"269","author":"A Feher","year":"2002","unstructured":"Feher A, Weber IT, Bagossi P, Boross P, Mahalingam B, Louis JM, Copeland TD, Torshin IY, Harrison RW, Tozser J: Effect of sequence polymorphism and drug resistance on two HIV-1 Gag processing sites. Eur J Biochem. 2002, 269: 4114-4120. 10.1046\/j.1432-1033.2002.03105.x.","journal-title":"Eur J Biochem"},{"key":"832_CR35","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/418144a","volume":"418","author":"A Jung","year":"2002","unstructured":"Jung A, Maier R, Vartanian JP, Bocharov G, Jung V, Fischer U, Meese E, Wain-Hobson S, Meyerhans A: Multiply infected spleen cells in HIV patients. Nature. 2002, 418: 144-10.1038\/418144a.","journal-title":"Nature"},{"key":"832_CR36","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1097\/QAD.0b013e3280121ac6","volume":"21","author":"KJ Metzner","year":"2007","unstructured":"Metzner KJ, Allers K, Rauch P, Harrer T: Rapid selection of drug-resistant HIV-1 during the first months of suppressive ART in treatment-naive patients. Aids. 2007, 21: 703-711. 10.1097\/QAD.0b013e3280121ac6.","journal-title":"Aids"},{"key":"832_CR37","unstructured":"Bayesian Evolutionary Analysis Sampling Trees. [http:\/\/beast.bio.ed.ac.uk]"},{"key":"832_CR38","doi-asserted-by":"publisher","first-page":"e88","DOI":"10.1371\/journal.pbio.0040088","volume":"4","author":"AJ Drummond","year":"2006","unstructured":"Drummond AJ, Ho SY, Phillips MJ, Rambaut A: Relaxed phylogenetics and dating with confidence. PLoS Biol. 2006, 4: e88-10.1371\/journal.pbio.0040088.","journal-title":"PLoS Biol"}],"container-title":["Retrovirology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1742-4690-5-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T09:48:17Z","timestamp":1630489697000},"score":1,"resource":{"primary":{"URL":"https:\/\/retrovirology.biomedcentral.com\/articles\/10.1186\/1742-4690-5-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,1,25]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2008,12]]}},"alternative-id":["832"],"URL":"https:\/\/doi.org\/10.1186\/1742-4690-5-7","relation":{},"ISSN":["1742-4690"],"issn-type":[{"value":"1742-4690","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,1,25]]},"assertion":[{"value":"10 October 2007","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2008","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2008","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"7"}}