DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions. Immunity 2018 Aug 21;49(2):235-246.e4
Date
08/05/2018Pubmed ID
30076100Pubmed Central ID
PMC6104740DOI
10.1016/j.immuni.2018.06.017Scopus ID
2-s2.0-85053816943 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
HIV-1 Envelope (Env) mediates viral-host membrane fusion after binding host-receptor CD4 and coreceptor. Soluble envelopes (SOSIPs), designed to mimic prefusion conformational states of virion-bound envelopes, are proposed immunogens for eliciting neutralizing antibodies, yet only static structures are available. To evaluate conformational landscapes of ligand-free, CD4-bound, inhibitor-bound, and antibody-bound SOSIPs, we measured inter-subunit distances throughout spin-labeled SOSIPs using double electron-electron resonance (DEER) spectroscopy and compared results to soluble and virion-bound Env structures, and single-molecule fluorescence resonance energy transfer (smFRET)-derived dynamics of virion-bound Envs. Unliganded SOSIP measurements were consistent with closed, neutralizing antibody-bound structures and shielding of non-neutralizing epitopes, demonstrating homogeneity at Env apex, increased flexibility near Env base, and no evidence for the intra-subunit flexibility near Env apex suggested by smFRET. CD4 binding increased inter-subunit distances and heterogeneity, consistent with rearrangements required for coreceptor binding. Results suggest similarities between SOSIPs and virion-bound Envs and demonstrate DEER's relevance for immunogen design.
Author List
Stadtmueller BM, Bridges MD, Dam KM, Lerch MT, Huey-Tubman KE, Hubbell WL, Bjorkman PJAuthor
Michael Lerch PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antibodies, NeutralizingBinding Sites, Antibody
CD4 Antigens
Cell Line
Electron Spin Resonance Spectroscopy
Epitopes
Fluorescence Resonance Energy Transfer
HEK293 Cells
HIV Antibodies
HIV Envelope Protein gp120
HIV Envelope Protein gp41
HIV-1
Humans
env Gene Products, Human Immunodeficiency Virus