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CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Ivan Branislav, Sun Zhaozhi, Subbaraman Harini, Friedrich Nikolas, Trkola Alexandra,
Project Understanding HIV-1 broadly neutralizing antibody evolution - The Swiss 4.5K Screen
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Original article (peer-reviewed)

Journal PLOS Biology
Volume (Issue) 17(1)
Page(s) e3000114 - e3000114
Title of proceedings PLOS Biology
DOI 10.1371/journal.pbio.3000114

Open Access

Type of Open Access Publisher (Gold Open Access)


During the entry process, the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer undergoes a sequence of conformational changes triggered by both CD4 and coreceptor engagement. Resolving the conformation of these transient entry intermediates has proven challenging. Here, we fine-mapped the antigenicity of entry intermediates induced by increasing CD4 engagement of cell surface–expressed Env. Escalating CD4 triggering led to the sequential adoption of different pre-fusion conformational states of the Env trimer, up to the pre-hairpin conformation, that we assessed for antibody epitope presentation. Maximal accessibility of the coreceptor binding site was detected below Env saturation by CD4. Exposure of the fusion peptide and heptad repeat 1 (HR1) required higher CD4 occupancy. Analyzing the diverse antigenic states of the Env trimer, we obtained key insights into the transitions in epitope accessibility of broadly neutralizing antibodies (bnAbs). Several bnAbs preferentially bound CD4-triggered Env, indicating a potential capacity to neutralize both pre- and post-CD4 engagement, which needs to be explored. Assessing binding and neutralization activity of bnAbs, we confirm antibody dissociation rates as a driver of incomplete neutralization. Collectively, our findings highlight a need to resolve Env conformations that are neutralization-relevant to provide guidance for immunogen development.