{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:14:42Z","timestamp":1790626482148,"version":"4.1.0"},"reference-count":102,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2013,1,1]],"date-time":"2013-01-01T00:00:00Z","timestamp":1356998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["#603708"],"award-info":[{"award-number":["#603708"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["#1006534"],"award-info":[{"award-number":["#1006534"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. National Institutes of Health\/NIAID","award":["R21 AI092218"],"award-info":[{"award-number":["R21 AI092218"]}]},{"DOI":"10.13039\/501100003969","name":"Iranian Ministry of Health and Medical Education","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003969","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sir Zelman Cowen Senior Research Fellow"},{"name":"Sir Zelman Cowen Fellowship Fund, Burnet Institute"},{"name":"Australian NHMRC Level 2 Biomedical Career Development Award"},{"name":"Australian NHMRC Early Career Research Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Along with an enhanced interaction with CD4, highly M-tropic HIV-1 Envs have an altered mechanism of engagement with CCR5.<\/jats:p>\n               <jats:p>BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. Second, BR-derived Envs displayed an altered mechanism of engagement between CD4-bound gp120 and CCR5 occurring in tandem. With the use of epitope mapping, mutagenesis, and structural studies, we show that this altered mechanism is characterized by increased exposure of CD4-induced epitopes in gp120 and by a more critical interaction between BR-derived Envs and the CCR5 N-terminus, which was associated with the predicted presence of additional atomic contacts formed at the gp120-CCR5 N-terminus interface. Our results suggest that BR-derived HIV-1 variants with highly efficient macrophage entry adopt conformations in gp120 that simultaneously alter the way in which the Env interacts with CD4 and CCR5.<\/jats:p>","DOI":"10.1189\/jlb.0612308","type":"journal-article","created":{"date-parts":[[2012,10,18]],"date-time":"2012-10-18T13:49:19Z","timestamp":1350568159000},"page":"113-126","source":"Crossref","is-referenced-by-count":36,"title":["Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5"],"prefix":"10.1093","volume":"93","author":[{"given":"Hamid","family":"Salimi","sequence":"first","affiliation":[{"name":"Centers for Virology, Burnet Institute , Melbourne, Victoria, Australia"},{"name":"Departments of Microbiology, Monash University , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Roche","sequence":"additional","affiliation":[{"name":"Centers for Virology, Burnet Institute , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Webb","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lachlan R","family":"Gray","sequence":"additional","affiliation":[{"name":"Centers for Virology, Burnet Institute , Melbourne, Victoria, Australia"},{"name":"Departments of Biochemistry, and Molecular Biology, Monash University , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelechi","family":"Chikere","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasminka","family":"Sterjovski","sequence":"additional","affiliation":[{"name":"Centers for Virology, Burnet Institute , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Ellett","sequence":"additional","affiliation":[{"name":"Centers for Virology, Burnet Institute , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve L","family":"Wesselingh","sequence":"additional","affiliation":[{"name":"South Australian Health and Medical Research Institute , Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A","family":"Ramsland","sequence":"additional","affiliation":[{"name":"Centers for Immunology, Burnet Institute , Melbourne, Victoria, Australia"},{"name":"Departments of Immunology, Monash University , Melbourne, Victoria, Australia"},{"name":"Departments of Surgery, Austin Health, and University of Melbourne , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benhur","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J","family":"Churchill","sequence":"additional","affiliation":[{"name":"Centers for Virology, Burnet Institute , Melbourne, Victoria, Australia"},{"name":"Departments of Microbiology, Monash University , Melbourne, Victoria, Australia"},{"name":"Departments of Medicine, Monash University , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R","family":"Gorry","sequence":"additional","affiliation":[{"name":"Centers for Virology, Burnet Institute , Melbourne, Victoria, Australia"},{"name":"Departments of Medicine, Monash University , Melbourne, Victoria, Australia"},{"name":"Departments of Microbiology and Immunology, University of Melbourne , Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,1,1]]},"reference":[{"key":"2023012312524016200_B1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nri1527","article-title":"The neuropathogenesis of AIDS","volume":"5","author":"Gonzalez-Scarano","year":"2005","journal-title":"Nat. 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Virol."},{"key":"2023012312524016200_B10","doi-asserted-by":"crossref","first-page":"10073","DOI":"10.1128\/JVI.75.21.10073-10089.2001","article-title":"Macrophage tropism of human immunodeficiency virus type 1 isolates from brain and lymphoid tissues predicts neurotropism independent of coreceptor specificity","volume":"75","author":"Gorry","year":"2001","journal-title":"J. Virol."},{"key":"2023012312524016200_B11","doi-asserted-by":"crossref","first-page":"6277","DOI":"10.1128\/JVI.76.12.6277-6292.2002","article-title":"Increased CCR5 affinity and reduced CCR5\/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate","volume":"76","author":"Gorry","year":"2002","journal-title":"J. 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