Author:
Julien Jean-Philippe,Lee Jeong Hyun,Ozorowski Gabriel,Hua Yuanzi,Torrents de la Peña Alba,de Taeye Steven W.,Nieusma Travis,Cupo Albert,Yasmeen Anila,Golabek Michael,Pugach Pavel,Klasse P. J.,Moore John P.,Sanders Rogier W.,Ward Andrew B.,Wilson Ian A.
Abstract
A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4 °C and 62.7 °C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.
Funder
HHS | NIH | National Institute of Allergy and Infectious Diseases
International AIDS Vaccine Initiative
Bill and Melinda Gates Foundation
Netherlands Organisation for Scientific Research | Technologiestichting STW
EC | European Research Council
California HIV/AIDS Research Program
Publisher
Proceedings of the National Academy of Sciences
Cited by
112 articles.
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