Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Sci Adv. 2018 Nov 21;4(11):eaau6769. doi: 10.1126/sciadv.aau6769. eCollection 2018 Nov.
Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41) is the main source of envelope metastability by replacing wild-type gp41 with BG505 gp41 of the uncleaved prefusion-optimized (UFO) design. These gp41-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder viruses and UFO trimers containing a consensus-based ancestral gp41 suggest an evolutionary root of metastability. The gp41-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers.
克服包膜的亚稳定性对于基于三聚体的 HIV-1 疫苗设计至关重要。在这里，我们通过最小化亚稳定性提出了一种连贯的疫苗策略。对于五个谱系中的 10 个株系，我们通过用未切割的前融合优化 (UFO) 设计的 BG505 gp41 取代野生型 gp41，证明 gp41 外域 (gp41) 是包膜亚稳定性的主要来源。这些 gp41 交换三聚体可以在 CHO 细胞中以高产率和高纯度生产。gp41 交换三聚体的晶体结构阐明了中和抗性第三层病毒如何逃避抗体对 V2 顶点的识别。传播/原始病毒的 UFO 三聚体和含有基于共识的祖先 gp41 的 UFO 三聚体表明亚稳定性的进化根源。gp41 稳定的三聚体可以很容易地在 24 聚体和 60 聚体纳米颗粒上展示，并且为超稳定的 60 聚体 I3-01 说明了加入额外的 T 细胞帮助。在小鼠和兔子中，这些 gp140 纳米颗粒比可溶性三聚体更有效地诱导了第二层中和抗体反应。
