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Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens

By Aleksandar Antanasijevic, George Ueda, Philip J.M. Brouwer, Jeffrey Copps, Deli Huang, Joel D Allen, Cristopher A. Cottrell, Anila Yasmeen, Leigh M. Sewall, Ilja Bontjer, Thomas J Ketas, Hannah L Turner, Zachary T Berndsen, Per Johan Klasse, Max Crispin, David Nemazee, John P Moore, Rogier W Sanders, Neil P. King, David Baker, Andrew B Ward

Posted 02 Feb 2020
bioRxiv DOI: 10.1101/2020.01.31.929273 (published DOI: 10.1371/journal.ppat.1008665)

Two-component, self-assembling nanoparticles represent a versatile platform for multivalent presentation of viral antigens. Nanoparticles of different sizes and geometries can be designed and combined with appropriate antigens to fit the requirements of different immunization strategies. Here, we describe detailed antigenic, structural, and functional characterization of computationally designed tetrahedral, octahedral, and icosahedral nanoparticle immunogens displaying trimeric HIV envelope glycoprotein (Env) ectodomains. Env trimers, based on subtype A (BG505) or consensus group M (ConM) sequences and engineered with SOSIP stabilizing mutations, were fused to the underlying trimeric building block of each nanoparticle. Initial screening yielded one icosahedral and two tetrahedral nanoparticle candidates, capable of presenting twenty or four copies of the Env trimer. A number of analyses, including detailed structural characterization by cryo-EM, demonstrated that the nanoparticle immunogens possessed the intended structural and antigenic properties. Comparing the humoral responses elicited by ConM-SOSIP trimers presented on a two-component tetrahedral nanoparticle to the corresponding soluble protein revealed that multivalent presentation increased the proportion of the overall antibody response directed against autologous neutralizing Ab epitopes present on the ConM-SOSIP trimers.

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