Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles.
Philip J M BrouwerAleksandar AntanasijevicMarlon de GastJoel D AllenTom P L BijlAnila YasmeenRashmi RavichandranJudith A BurgerGabriel OzorowskiJonathan L TorresCelia C LaBrancheDavid C MontefioriRajesh P RingeMarit J van GilsJohn P MoorePer Johan KlasseMax CrispinNeil P KingAndrew B WardRogier W SandersPublished in: NPJ vaccines (2021)
The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display are generally modest for Env trimers. Here, we generate two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. We show in a rabbit immunization study that these nanoparticles induce 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping studies reveal that the presentation of 16055 SOSIP trimers on these nanoparticle focuses antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- hepatitis c virus
- immune response
- hiv aids
- men who have sex with men
- advanced non small cell lung cancer
- case report
- escherichia coli
- walled carbon nanotubes
- bone marrow
- high throughput
- toll like receptor
- south africa
- genome wide
- gene expression
- small molecule
- cell therapy
- monoclonal antibody
- dendritic cells
- tyrosine kinase
- high density
- cell surface
- dengue virus