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|Title:||Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5|
|Citation:||Journal of Leukocyte Biology, 2013; 93(1):113-126|
|Publisher:||Society for Leukocyte Biology|
|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|
|Appears in Collections:||Medicine publications|
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