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https://hdl.handle.net/2440/100136
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Type: | Journal article |
Title: | Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5 |
Author: | Salimi, H. Roche, M. Webb, N. Gray, L. Chikere, K. Sterjovski, J. Ellett, A. Wesselingh, S. Ramsland, P. Lee, B. Churchill, M. Gorry, P. |
Citation: | Journal of Leukocyte Biology, 2013; 93(1):113-126 |
Publisher: | Society for Leukocyte Biology |
Issue Date: | 2013 |
ISSN: | 0741-5400 1938-3673 |
Statement of Responsibility: | 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 |
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. |
Keywords: | Env; affinofile; CNS; signature; phenotype |
Rights: | © Society for Leukocyte Biology |
DOI: | 10.1189/jlb.0612308 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/603708 http://purl.org/au-research/grants/nhmrc/1006534 |
Published version: | http://dx.doi.org/10.1189/jlb.0612308 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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