{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:19:22Z","timestamp":1785406762978,"version":"3.56.0"},"reference-count":18,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["Operating grant"],"award-info":[{"award-number":["Operating grant"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CIHR Team","award":["197728"],"award-info":[{"award-number":["197728"]}]},{"name":"CHIR project","award":["451304"],"award-info":[{"award-number":["451304"]}]},{"DOI":"10.13039\/501100001805","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","award":["41027"],"award-info":[{"award-number":["41027"]}],"id":[{"id":"10.13039\/501100001805","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI162646, UM1AI144371, UM1AI164570"],"award-info":[{"award-number":["R01 AI162646, UM1AI144371, UM1AI164570"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FRQS and CIHR master\u2019s fellowships"},{"name":"CIHR doctoral fellowship"},{"name":"MITACS Elevation post-doctoral fellowship"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,10,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>HIV-1-mediated CD4 downregulation is a well-known mechanism that protects infected cells from antibody-dependent cellular cytotoxicity (ADCC). While CD4 downregulation by HIV-1 Nef and Vpu proteins has been extensively studied, the contribution of the HIV-1 envelope glycoprotein (Env) in this mechanism is less understood. While Env is known to retain CD4 in the endoplasmic reticulum (ER) through its CD4-binding site (CD4bs), little is known about the mechanisms underlying this process. Here, we show that the cytoplasmic tail of Env is a major determinant in CD4 downregulation. This function is highly conserved as it was observed with nine different infectious molecular clones from four clades. The small but significant accumulation of CD4 at the surface of cells infected with Env cytoplasmic tail-deleted viruses is sufficient to trigger Env to adopt a more \u201copen\u201d conformation. This prompted recognition of HIV-1-infected cells by plasma from people living with HIV (PLWH) and several families of CD4-induced (CD4i) antibodies, leading to the elimination of these cells by ADCC. While cytoplasmic tail truncations are known to enhance Env expression at the cell surface, this did not fully explain the increased recognition of infected cells by CD4i antibodies and plasma from PLWH. Introduction of the CD4bs D368R mutation, which abrogates CD4 interaction, decreased Env recognition and ADCC. Overall, our results show that CD4 downregulation by the cytoplasmic tail of Env contributes to the protection of infected cells from ADCC.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>HIV-1-mediated CD4 downregulation is a central mechanism involved in the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC). CD4 downregulation prevents the premature interaction between HIV-1 envelope glycoproteins (Env) and CD4, which would otherwise \u201copen\u201d Env and expose vulnerable epitopes recognized by CD4-induced antibodies present in the plasma from people living with HIV. While the mechanisms of CD4 downregulation by the viral accessory proteins Nef and Vpu have been elucidated, the function of Env in this process is less clear. Here, we show that the cytoplasmic tail of Env plays an important role, thus contributing to the protection of infected cells from ADCC.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01763-25","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T12:00:29Z","timestamp":1757332829000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["The HIV-1 envelope cytoplasmic tail protects infected cells from ADCC by downregulating CD4"],"prefix":"10.1128","volume":"16","author":[{"given":"Alexandra","family":"Tauzin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rgqcd02","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Recherche du CHUM","place":["Montreal, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9tienne","family":"B\u00e9langer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rgqcd02","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Recherche du CHUM","place":["Montreal, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00e9mie","family":"Pr\u00e9vost","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rgqcd02","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Recherche du CHUM","place":["Montreal, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halima","family":"Medjahed","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rgqcd02","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Recherche du CHUM","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Bourassa","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rgqcd02","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Recherche du CHUM","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Bibollet-Ruche","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00wd70b02","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Pennsylvania","place":["Philadelphia, USA"]},{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, University of Pennsylvania","place":["Philadelphia, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-9589","authenticated-orcid":true,"given":"Jonathan","family":"Richard","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rgqcd02","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Recherche du CHUM","place":["Montreal, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice H.","family":"Hahn","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00wd70b02","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Pennsylvania","place":["Philadelphia, USA"]},{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, University of Pennsylvania","place":["Philadelphia, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-5288","authenticated-orcid":true,"given":"Andr\u00e9s","family":"Finzi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04rgqcd02","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre de Recherche du CHUM","place":["Montreal, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"D\u00e9partement de Microbiologie, Infectiologie et Immunologie, Universit\u00e9 de Montr\u00e9al","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03230-13"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02868-14"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2017.10.007"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90360-3"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.5.3157"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00548-09"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.66.12.7193-7200.1992"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000869"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.70.9.6044-6053.1996"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00252-06"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111983"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.66.8.4966-4971.1992"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02053-12"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.25.15773"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01911-15"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00219-17"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3791\/51995"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.03.002"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01763-25","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01763-25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T13:04:47Z","timestamp":1759928687000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.01763-25"}},"subtitle":[],"editor":[{"given":"Alan N.","family":"Engelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":18,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,8]]}},"alternative-id":["10.1128\/mbio.01763-25"],"URL":"https:\/\/doi.org\/10.1128\/mbio.01763-25","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.06.06.658250","asserted-by":"object"}]},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]},"assertion":[{"value":"2025-06-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01763-25"}}