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首页> 美国卫生研究院文献>ACS AuthorChoice >Design of Lipid Nanocapsule Delivery Vehicles forMultivalent Display of Recombinant Env Trimers in HIV Vaccination
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Design of Lipid Nanocapsule Delivery Vehicles forMultivalent Display of Recombinant Env Trimers in HIV Vaccination

机译：脂质纳米胶囊载药载体的设计。HIV疫苗中重组Env三聚体的多价展示

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Immunization strategies that elicit antibodies capable of neutralizing diverse virus strains will likely be an important part of a successful vaccine against HIV. However, strategies to promote robust humoral responses against the native intact HIV envelope trimer structure are lacking. We recently developed chemically cross-linked lipid nanocapsules as carriers of molecular adjuvants and encapsulated or surface-displayed antigens, which promoted follicular helper T-cell responses and elicited high-avidity, durable antibody responses to a candidate malaria antigen. To apply this system to the delivery of HIV antigens, Env gp140 trimers with terminal his-tags (gp140T-his) were anchored to the surface of lipid nanocapsules via Ni-NTA-functionalized lipids. Initial experiments revealed that the large (409 kDa), heavily glycosylated trimers were capable of extracting fluid phase lipids from the membranes of nanocapsules. Thus, liquid-ordered and/or gel-phase lipid compositions were required to stably anchor trimers to the particle membranes. Trimer-loaded nanocapsules combined with the clinically relevant adjuvant monophosphoryllipid A primed high-titer antibody responses in mice at antigen dosesranging from 5 μg to as low as 100 ng, whereas titers droppedmore than 50-fold over the same dose range when soluble trimer wasmixed with a strong oil-in-water adjuvant comparator. Nanocapsuleimmunization also broadened the number of distinct epitopes on theHIV trimer recognized by the antibody response. These results suggestthat nanocapsules displaying HIV trimers in an oriented, multivalentpresentation can promote key aspects of the humoral response againstEnv immunogens.
机译：引发能够中和多种病毒株的抗体的免疫策略可能将是成功的抗HIV疫苗的重要组成部分。然而，缺乏促进针对天然完整的HIV包膜三聚体结构的强烈体液反应的策略。我们最近开发了化学交联的脂质纳米胶囊作为分子佐剂和封装的或表面展示的抗原的载体，从而促进了滤泡辅助性T细胞反应并引发了对候选疟疾抗原的高亲和力，持久性抗体反应。为了将该系统应用于HIV抗原的传递，带有末端组氨酸标签的Env gp140三聚体（gp140T-his）通过Ni-NTA功能化的脂质锚定在脂质纳米胶囊的表面。最初的实验表明，大的（409 kDa），高度糖基化的三聚体能够从纳米胶囊的膜中提取液相脂质。因此，需要液体有序和/或凝胶相脂质组合物以将三聚体稳定地锚定至颗粒膜。三聚体负载的纳米胶囊与临床相关的佐剂单磷酸结合抗原剂量下脂质A引发的高滴度抗体应答范围从5μg至低至100 ng，滴度下降当可溶性三聚体为相同剂量范围时，在相同剂量范围内超过50倍与强大的水包油佐剂比较剂混合。纳米胶囊免疫接种还扩大了小鼠表皮上不同表位的数量。HIV三聚体被抗体反应识别。这些结果表明纳米胶囊以定向的多价展示HIV三聚体演讲可以促进针对性的体液反应的关键方面Env免疫原。

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