{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:59:02Z","timestamp":1790272742537,"version":"4.1.0"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T00:00:00Z","timestamp":1506384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T00:00:00Z","timestamp":1510099200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"ViiV Healthcare France"},{"name":"The Agence Nationale de Recherche sur le SIDA"},{"name":"The association de Recherche en Virologie et Dermatologie"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2017,11,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Resistance to the integrase strand transfer inhibitors raltegravir and elvitegravir is often due to well-identified mutations in the integrase gene. However, the situation is less clear for patients who fail dolutegravir treatment. Furthermore, most<jats:italic>in vitro<\/jats:italic>experiments to select resistance to dolutegravir have resulted in few mutations of the integrase gene. We performed an<jats:italic>in vitro<\/jats:italic>dolutegravir resistance selection experiment by using a breakthrough method. First, MT4 cells were infected with human immunodeficiency virus type 1 (HIV-1) Lai. After integration into the host cell genome, cells were washed to remove unbound virus and 500\u00a0nM dolutegravir was added to the cell medium. This high concentration of the drug was maintained throughout selection. At day 80, we detected a virus highly resistant to dolutegravir, raltegravir, and elvitegravir that remained susceptible to zidovudine. Sequencing of the virus showed no mutations in the integrase gene but highlighted the emergence of five mutations, all located in the<jats:italic>nef<\/jats:italic>region, of which four were clustered in the 3\u2032 polypurine tract (PPT). Mutations selected<jats:italic>in vitro<\/jats:italic>by dolutegravir, located outside the integrase gene, can confer a high level of resistance to all integrase inhibitors. Thus, HIV-1 can use an alternative mechanism to develop resistance to integrase inhibitors by selecting mutations in the 3\u2032 PPT region. Further studies are required to determine to what extent these mutations may explain virological failure during integrase inhibitor therapy.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Integrase strand transfer inhibitors (INSTIs) are increasingly used both as first-line drugs and in rescue therapy because of their low toxicity and high efficacy in both treatment-naive and treatment-experienced patients. Until now, resistance mutations selected by INSTI exposure have either been described in patients or selected<jats:italic>in vitro<\/jats:italic>and involve the integrase gene. Most mutations selected by raltegravir, elvitegravir, or dolutegravir exposure are located inside the catalytic site of the integrase gene, but mutations outside the catalytic site of the integrase gene have also been selected with dolutegravir. Following<jats:italic>in vitro<\/jats:italic>selection with dolutegravir, we report, for the first time, a virus with selected mutations outside the HIV-1 integrase gene that confer resistance to all integrase inhibitors currently used to treat patients, such as raltegravir, elvitegravir, and dolutegravir. Our observation may explain why some viruses responsible for virological failure in patients treated with dolutegravir did not show mutations in the integrase gene.<\/jats:p>","DOI":"10.1128\/mbio.00922-17","type":"journal-article","created":{"date-parts":[[2017,9,27]],"date-time":"2017-09-27T00:10:52Z","timestamp":1506471052000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":93,"title":["Mutations Located outside the Integrase Gene Can Confer Resistance to HIV-1 Integrase Strand Transfer Inhibitors"],"prefix":"10.1128","volume":"8","author":[{"given":"Isabelle","family":"Malet","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, Institut Pierre Louis d\u2019Epid\u00e9miologie et de Sant\u00e9 Publique (IPLESP UMRS 1136), Paris, France"},{"name":"Department of Virology, AP-HP, H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Subra","sequence":"additional","affiliation":[{"name":"LBPA, ENS Cachan, CNRS UMR 8113, IDA, FR3242, Universit\u00e9 Paris-Saclay, Cachan, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Charpentier","sequence":"additional","affiliation":[{"name":"INSERM, IAME, UMR1137, Paris, France"},{"name":"Universit\u00e9 Paris Diderot, IAME, UMR1137, Sorbonne Paris Cit\u00e9, Paris, France"},{"name":"AP-HP, H\u00f4pital Bichat, Laboratoire de Virologie, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Collin","sequence":"additional","affiliation":[{"name":"INSERM, IAME, UMR1137, Paris, France"},{"name":"Universit\u00e9 Paris Diderot, IAME, UMR1137, Sorbonne Paris Cit\u00e9, Paris, France"},{"name":"AP-HP, H\u00f4pital Bichat, Laboratoire de Virologie, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Descamps","sequence":"additional","affiliation":[{"name":"INSERM, IAME, UMR1137, Paris, France"},{"name":"Universit\u00e9 Paris Diderot, IAME, UMR1137, Sorbonne Paris Cit\u00e9, Paris, France"},{"name":"AP-HP, H\u00f4pital Bichat, Laboratoire de Virologie, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Calvez","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, Institut Pierre Louis d\u2019Epid\u00e9miologie et de Sant\u00e9 Publique (IPLESP UMRS 1136), Paris, France"},{"name":"Department of Virology, AP-HP, H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Genevi\u00e8ve","family":"Marcelin","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, INSERM, Institut Pierre Louis d\u2019Epid\u00e9miologie et de Sant\u00e9 Publique (IPLESP UMRS 1136), Paris, France"},{"name":"Department of Virology, AP-HP, H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Delelis","sequence":"additional","affiliation":[{"name":"LBPA, ENS Cachan, CNRS UMR 8113, IDA, FR3242, Universit\u00e9 Paris-Saclay, Cachan, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2004.02.016"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.43.2.482-488.1982"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-76-7-1675"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2014.12.001"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00157-11"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.111.073189"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm800245z"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60597-2"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0708978"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01228-07"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01075-09"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku535"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkv149"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0213-005X(15)30006-9"},{"key":"e_1_3_2_16_2","volume-title":"Conference on Retroviruses and Opportunistic Infections","author":"Blanco JL","year":"2017","unstructured":"Blanco JL Oldenbuettel C Thomas R Mallolas J Wolf E Brenner BG Spinner CD Wainberg MA Martinez E . 2017. 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