Recombinant HIV-1 envelope (Env) glycoproteins of ever-increasing sophistication have been evaluated as vaccine candidates for over 30 years. Structurally defined mimics of native trimeric Env glycoproteins (e.g., SOSIP trimers) present multiple epitopes for broadly neutralizing antibodies (bNAbs) and their germline precursors, but elicitation of bNAbs remains elusive. Here, we argue that the interactions between Env and the immune system render it exceptional among viral vaccine antigens and hinder its immunogenicity in absolute and comparative terms. In other words, Env binds to CD4 on key immune cells and transduces signals that can compromise their function. Moreover, the extensive array of oligomannose glycans on Env shields peptidic B cell epitopes, impedes the presentation of T helper cell epitopes, and attracts mannose binding proteins, which could affect the antibody response. We suggest lines of research for assessing how to overcome obstacles that the exceptional features of Env impose on the creation of a successful HIV-1 vaccine.

中文翻译：

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Env 例外论：为什么 HIV-1 Env 糖蛋白是非典型免疫原？


30 多年来，日益复杂的重组 HIV-1 包膜 (Env) 糖蛋白一直被作为候选疫苗进行评估。天然三聚体 Env 糖蛋白（例如 SOSIP 三聚体）的结构定义模拟物呈现广泛中和抗体 (bNAb) 及其种系前体的多个表位，但 bNAb 的诱导仍然难以捉摸。在这里，我们认为 Env 与免疫系统之间的相互作用使其在病毒疫苗抗原中脱颖而出，并在绝对和比较方面阻碍了其免疫原性。换句话说，Env 与关键免疫细胞上的 CD4 结合并转导可能损害其功能的信号。此外，Env 上大量的寡甘露糖聚糖可屏蔽肽 B 细胞表位，阻碍 T 辅助细胞表位的呈递，并吸引甘露糖结合蛋白，这可能会影响抗体反应。我们建议进行一系列研究来评估如何克服 Env 的特殊特征对成功研制 HIV-1 疫苗造成的障碍。