Brouwer Philip J M, Antanasijevic Aleksandar, de Gast Marlon, Allen Joel D, Bijl Tom P L, Yasmeen Anila, Ravichandran Rashmi, Burger Judith A, Ozorowski Gabriel, Torres Jonathan L, LaBranche Celia, Montefiori David C, Ringe Rajesh P, van Gils Marit J, Moore John P, Klasse Per Johan, Crispin Max, King Neil P, Ward Andrew B, Sanders Rogier W
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
NPJ Vaccines. 2021 Feb 9;6(1):24. doi: 10.1038/s41541-021-00285-9.
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.
HIV-1包膜糖蛋白三聚体免疫原性较差，因为它被一层密集的聚糖屏蔽所覆盖。因此，重组Env糖蛋白通常引发的抗体水平不足以中和临床上相关的、具有中和抗性的（2级）HIV-1毒株。纳米颗粒上的多价抗原呈递是一种已确立的增强疫苗驱动免疫反应的策略。然而，由于纳米颗粒在体内的不稳定性、非天然Env结构的展示以及许多中和抗体（NAb）表位难以接近，纳米颗粒展示对Env三聚体的影响通常较为有限。在此，我们生成了呈现C亚型2级基因型16055的20个SOSIP三聚体的双组分自组装蛋白纳米颗粒。我们在一项兔免疫研究中表明，这些纳米颗粒诱导的自体2级NAb滴度比相应的SOSIP三聚体高60倍。表位作图研究表明，这些纳米颗粒上16055 SOSIP三聚体的呈递使抗体反应集中于一个免疫显性顶端表位。因此，这些纳米颗粒是一个有前景的平台，可提高具有靠近顶端NAb表位的Env三聚体的免疫原性。
