{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T18:20:28Z","timestamp":1784917228674,"version":"3.55.0"},"reference-count":89,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T00:00:00Z","timestamp":1488326400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Interactions between the gp120 and gp41 subunits of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer maintain the metastable unliganded form of the viral spike. Binding of gp120 to the receptor, CD4, changes the Env conformation to promote gp120 interaction with the second receptor, CCR5 or CXCR4. CD4 binding also induces the transformation of Env into the prehairpin intermediate, in which the gp41 heptad repeat 1 (HR1) coiled coil is assembled at the trimer axis. In nature, HIV-1 Envs must balance the requirements to maintain the noncovalent association of gp120 with gp41 and to evade the host antibody response with the need to respond to CD4 binding. Here we show that the gp41 HR1 region contributes to gp120 association with the unliganded Env trimer. Changes in particular amino acid residues in the gp41 HR1 region decreased the efficiency with which Env moved from the unliganded state. Thus, these gp41 changes decreased the sensitivity of HIV-1 to cold inactivation and ligands that require Env conformational changes to bind efficiently. Conversely, these gp41 changes increased HIV-1 sensitivity to small-molecule entry inhibitors that block Env conformational changes induced by CD4. Changes in particular gp41 HR1 amino acid residues can apparently affect the relative stability of the unliganded state and CD4-induced conformations. Thus, the gp41 HR1 region contributes to the association with gp120 and regulates Env transitions from the unliganded state to downstream conformations.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The development of an efficient vaccine able to prevent HIV infection is a worldwide priority. Knowledge of the envelope glycoprotein structure and the conformational changes that occur after receptor engagement will help researchers to develop an immunogen able to elicit antibodies that block HIV-1 transmission. Here we identify residues in the HIV-1 transmembrane envelope glycoprotein that stabilize the unliganded state by modulating the transitions from the unliganded state to the CD4-bound state.<\/jats:p>","DOI":"10.1128\/jvi.02219-16","type":"journal-article","created":{"date-parts":[[2016,12,22]],"date-time":"2016-12-22T02:27:36Z","timestamp":1482373656000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":65,"title":["Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors"],"prefix":"10.1128","volume":"91","author":[{"given":"Beatriz","family":"Pacheco","sequence":"first","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmin","family":"Alsahafi","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olfa","family":"Debbeche","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Microbiology, Infectiology, and Immunology, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00e9mie","family":"Pr\u00e9vost","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Microbiology, Infectiology, and Immunology, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilei","family":"Ding","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Microbiology, Infectiology, and Immunology, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Chapleau","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Microbiology, Infectiology, and Immunology, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alon","family":"Herschhorn","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navid","family":"Madani","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Princiotto","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Melillo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youdong","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Amos B.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Sodroski","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"},{"name":"Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA"},{"name":"Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Finzi","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l'Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, Canada"},{"name":"Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada"},{"name":"Department of Microbiology, Infectiology, and Immunology, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2986290"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2984774"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80205-6"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.9.7620-7625.1998"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/387426a0"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2634931100"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.65.4.2119-2123.1991"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/312763a0"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/312767a0"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5270.1955"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81313-6"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/381661a0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81314-8"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/381667a0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5263.872"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/384179a0"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/384184a0"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0498-276"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.3.1666-1671.2003"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211154200"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307953101"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254426"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01598-16"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb1295-1075"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0042-6822(03)00273-3"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.02.012"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.12.001"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.67.5.2747-2755.1993"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.14.6635-6644.2001"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M305223200"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi1005267"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90179-1"},{"key":"e_1_3_2_34_2","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.4049\/jimmunol.137.10.3306","article-title":"In vitro generation of an HTLV-III variant by neutralizing antibody","volume":"137","author":"Robert-Guroff M","year":"1986","unstructured":"Robert-Guroff M Reitz MS Jr Robey WG Gallo RC . 1986. In vitro generation of an HTLV-III variant by neutralizing antibody. J Immunol 137:3306\u20133309.","journal-title":"J Immunol"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.64.7.3240-3248.1990"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002101"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.2.674-680.1994"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1112391109"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1993.1484"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.69.3.1860-1867.1995"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.70.12.8431-8437.1996"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.08.045"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00666-08"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.10.006"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307382110"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1245625"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02587-09"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13808"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad2450"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.3.2041-2049.1997"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.9.4921-4926.2004"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911004107"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01068-16"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03104-12"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.23.12303"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0050009"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.67.11.6897-6902.1993"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi061193r"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2008.09.005"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1021\/ml300407y"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00540-14"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00594-09"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1623"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000360"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02110-08"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.19.9888-9899.2002"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.7.3435-3443.2001"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.2.644-655.2002"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200302140-00002"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.6.2595-2605.2002"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2351"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1245627"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2711"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.11.5091-5100.2000"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.17.8875-8889.2002"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003618"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.2.627-643.2000"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01226-13"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00494-14"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122111"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07159"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1615939113"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.09.032"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037157"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf7066"},{"key":"e_1_3_2_86_2","volume-title":"Theoretical Biology and Biophysics","author":"Foley B","year":"2013","unstructured":"Foley B Leitner T Apetrei C Hahn B Mizrachi I Mullins J Rambaut A Wolinsky S Korber B (ed). 2013. HIV sequence compendium. LA-UR-13-26007. Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM."},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.4.2855-2864.1998"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.22.10690-10698.2000"},{"key":"e_1_3_2_89_2","volume-title":"The Human Retroviruses and AIDS 1998 Compendium, part III, Analyses","author":"Korber B","year":"1998","unstructured":"Korber B Foley BT Kuiken C Pillai SK Sodroski JG . 1998. Numbering positions in HIV relative to HXB2CG. The Human Retroviruses and AIDS 1998 Compendium, part III, Analyses. Los Alamos National Laboratory, Los Alamos, NM. https:\/\/hfv.lanl.gov\/content\/sequence\/HIV\/COMPENDIUM\/98compendium.html ."},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(81)90642-5"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.02219-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.02219-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T11:35:41Z","timestamp":1692617741000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.02219-16"}},"subtitle":[],"editor":[{"given":"Guido","family":"Silvestri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2017,3]]},"references-count":89,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,3]]}},"alternative-id":["10.1128\/JVI.02219-16"],"URL":"https:\/\/doi.org\/10.1128\/jvi.02219-16","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3]]},"assertion":[{"value":"2016-11-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-12-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-02-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02219-16"}}