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 Pathogjournal_title
PLoS pathogensauthors
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 Ddoi
10.1371/journal.ppat.1008665subject
Has Abstractpub_date
2020-08-11 00:00:00pages
e1008665issue
8eissn
1553-7366issn
1553-7374pii
PPATHOGENS-D-20-00236journal_volume
16pub_type
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