Gonelli Christopher A, King Hannah A D, Mackenzie Charlene, Sonza Secondo, Center Rob J, Purcell Damian F J
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia.
Viral Entry and Vaccines Laboratory, Disease Elimination, Burnet Institute, Melbourne, VIC 3004, Australia.
Vaccines (Basel). 2021 Mar 10;9(3):239. doi: 10.3390/vaccines9030239.
An optimal prophylactic vaccine to prevent human immunodeficiency virus (HIV-1) transmission should elicit protective antibody responses against the HIV-1 envelope glycoprotein (Env). Replication-incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present virion-associated Env with a native-like structure during vaccination that closely resembles that encountered on infectious virus. Here, we optimized the incorporation of Env into previously designed mature-form VLPs (mVLPs) and assessed their immunogenicity in mice. The incorporation of Env into mVLPs was increased by replacing the Env transmembrane and cytoplasmic tail domains with those of influenza haemagglutinin (HA-TMCT). Furthermore, Env was stabilized on the VLP surface by introducing an interchain disulfide and proline substitution (SOSIP) mutations typically employed to stabilize soluble Env trimers. The resulting mVLPs efficiently presented neutralizing antibody epitopes while minimizing exposure of non-neutralizing antibody sites. Vaccination of mice with mVLPs elicited a broader range of Env-specific antibody isotypes than Env presented on immature VLPs or extracellular vesicles. The mVLPs bearing HA-TMCT-modified Env consistently induced anti-Env antibody responses that mediated modest neutralization activity. These mVLPs are potentially useful immunogens for eliciting neutralizing antibody responses that target native Env epitopes on infectious HIV-1 virions.
一种用于预防人类免疫缺陷病毒（HIV-1）传播的最佳预防性疫苗应能引发针对HIV-1包膜糖蛋白（Env）的保护性抗体反应。无复制能力的HIV-1病毒样颗粒（VLP）为在疫苗接种过程中呈现具有天然样结构的病毒体相关Env提供了机会，这种结构与感染性病毒上的结构极为相似。在此，我们优化了Env在先前设计的成熟形式VLP（mVLP）中的掺入，并评估了它们在小鼠体内的免疫原性。通过用流感血凝素（HA-TMCT）的跨膜和细胞质尾域替换Env的相应区域，Env在mVLP中的掺入量增加。此外，通过引入通常用于稳定可溶性Env三聚体的链间二硫键和脯氨酸取代（SOSIP）突变，Env在VLP表面得以稳定。所得的mVLP有效地呈现了中和抗体表位，同时将非中和抗体位点的暴露降至最低。用mVLP对小鼠进行疫苗接种所引发的Env特异性抗体同种型范围比在未成熟VLP或细胞外囊泡上呈现的Env更广泛。带有HA-TMCT修饰Env的mVLP始终诱导出介导适度中和活性的抗Env抗体反应。这些mVLP可能是用于引发针对感染性HIV-1病毒体上天然Env表位的中和抗体反应的有用免疫原。
