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https://hdl.handle.net/2440/100136
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dc.contributor.author | Salimi, H. | - |
dc.contributor.author | Roche, M. | - |
dc.contributor.author | Webb, N. | - |
dc.contributor.author | Gray, L. | - |
dc.contributor.author | Chikere, K. | - |
dc.contributor.author | Sterjovski, J. | - |
dc.contributor.author | Ellett, A. | - |
dc.contributor.author | Wesselingh, S. | - |
dc.contributor.author | Ramsland, P. | - |
dc.contributor.author | Lee, B. | - |
dc.contributor.author | Churchill, M. | - |
dc.contributor.author | Gorry, P. | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Journal of Leukocyte Biology, 2013; 93(1):113-126 | - |
dc.identifier.issn | 0741-5400 | - |
dc.identifier.issn | 1938-3673 | - |
dc.identifier.uri | http://hdl.handle.net/2440/100136 | - |
dc.description.abstract | 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. | - |
dc.description.statementofresponsibility | Hamid Salimi, Michael Roche, Nicholas Webb, Lachlan R. Gray, Kelechi Chikere, Jasminka Sterjovski, Anne Ellett, Steve L. Wesselingh, Paul A. Ramsland, Benhur Lee, Melissa J. Churchill, and Paul R. Gorry | - |
dc.language.iso | en | - |
dc.publisher | Society for Leukocyte Biology | - |
dc.rights | © Society for Leukocyte Biology | - |
dc.source.uri | http://dx.doi.org/10.1189/jlb.0612308 | - |
dc.subject | Env; affinofile; CNS; signature; phenotype | - |
dc.title | Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5 | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1189/jlb.0612308 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/603708 | - |
dc.relation.grant | http://purl.org/au-research/grants/nhmrc/1006534 | - |
pubs.publication-status | Published | - |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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