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

Abstract:

:Two-component, self-assembling nanoparticles represent a versatile platform for multivalent presentation of viral antigens. Computational design of protein nanoparticles with differing sizes and geometries enables combination with antigens of choice to test novel multimerization concepts in immunization strategies where the goal is to improve the induction and maturation of neutralizing antibody lineages. 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 an 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. When the immunogenicity of ConM-SOSIP trimers presented on a two-component tetrahedral nanoparticle or as soluble proteins were compared in rabbits, the two immunogens elicited similar serum antibody binding titers against the trimer component. Neutralizing antibody titers were slightly elevated in the animals given the nanoparticle immunogen and were initially more focused to the trimer apex. Altogether, our findings indicate that tetrahedral nanoparticles can be successfully applied for presentation of HIV Env trimer immunogens; however, the optimal implementation to different immunization strategies remains to be determined.

journal_name

PLoS Pathog

journal_title

PLoS pathogens

authors

Antanasijevic A,Ueda G,Brouwer PJM,Copps J,Huang D,Allen JD,Cottrell CA,Yasmeen A,Sewall LM,Bontjer I,Ketas TJ,Turner HL,Berndsen ZT,Montefiori DC,Klasse PJ,Crispin M,Nemazee D,Moore JP,Sanders RW,King NP,Baker D

doi

10.1371/journal.ppat.1008665

subject

Has Abstract

pub_date

2020-08-11 00:00:00

pages

e1008665

issue

8

eissn

1553-7366

issn

1553-7374

pii

PPATHOGENS-D-20-00236

journal_volume

16

pub_type

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