Macrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5

作者：Salimi Hamid; Roche Michael; Webb Nicholas; Gray Lachlan R; Chikere Kelechi; Sterjovski Jasminka; Ellett Anne; Wesselingh Steve L; Ramsland Paul A; Lee Benhur; Churchill Melissa J; Gorry Paul R^*

来源：Journal of Leukocyte Biology, 2013, 93(1): 113-126.

DOI：10.1189/jlb.0612308

• Env
• Affinofile
• CNS
• signature
• phenotype

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. J. Leukoc. Biol. 93: 113-126; 2013.

• 出版日期2013-1