Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles

• Published in: Nature structural & molecular biology Vol. 27; no. 8; pp. 726 - 734
• Main Authors: Li, Ze, Li, Wenwei, Lu, Maolin, Bess, Jr, Julian, Chao, Cara W, Gorman, Jason, Terry, Daniel S, Zhang, Baoshan, Zhou, Tongqing, Blanchard, Scott C, Kwong, Peter D, Lifson, Jeffrey D, Mothes, Walther, Liu, Jun
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.08.2020
• Subjects: 2,2'-Dipyridyl - analogs & derivatives; 2,2'-Dipyridyl - pharmacology; Antibodies; Binding sites; Cancer; CD4 antigen; Cell Line; Cryoelectron Microscopy; Deactivation; Disulfides - pharmacology; Electron Microscope Tomography; Glycoprotein gp120; Glycoprotein gp41; Glycoproteins; HIV; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - ultrastructure; HIV Envelope Protein gp41 - chemistry; HIV Envelope Protein gp41 - ultrastructure; HIV Infections - virology; HIV-1 - chemistry; HIV-1 - drug effects; Human immunodeficiency virus; Humans; Inactivation; Ligands; Medical research; Models, Molecular; Molecular biology; Oxidants - pharmacology; Protein Conformation - drug effects; Protein Multimerization - drug effects; Solubility; Trimers; Virion - chemistry; Virion - drug effects; Virions; Viruses
• ISSN: 1545-9993; 1545-9985; 1545-9985
• DOI: 10.1038/s41594-020-0452-2

The HIV-1 envelope glycoprotein (Env) trimer, composed of gp120 and gp41 subunits, mediates viral entry into cells. Recombinant Env trimers have been studied structurally, but characterization of Env embedded in intact virus membranes has been limited to low resolution. Here, we deploy cryo-electron tomography and subtomogram averaging to determine the structures of Env trimers on aldrithiol-2 (AT-2)-inactivated virions in ligand-free, antibody-bound and CD4-bound forms at subnanometer resolution. Tomographic reconstructions document molecular features consistent with high-resolution structures of engineered soluble and detergent-solubilized Env trimers. One of three conformational states previously predicted by smFRET was not observed by cryo-ET, potentially owing to AT-2 inactivation. We did observe Env trimers to open in situ in response to CD4 binding, with an outward movement of gp120-variable loops and an extension of a critical gp41 helix. Overall features of Env trimer embedded in AT-2-treated virions appear well-represented by current engineered trimers.