HIV neutralization and mechanisms of cellular entry

了解完整病毒上三聚体Env的分子结构和描述细胞-细胞传播机制是设计有效的免疫原和治疗药物以对抗艾滋病毒/艾滋病的核心。过去一年，我们继续朝着这些目标取得重大进展。我们在过去一年中取得的主要进展包括：(i)发现了参与介导HIV在不同类型细胞-细胞接触（包括t - t细胞和t -树突状细胞突触）之间传播的病毒学突触类型的变化；（ii）来自大量病毒株和可溶性免疫原的三聚体HIV-1和SIV包膜糖蛋白的分子结构；（iii）证明可溶性gp140免疫原可以显示与天然包膜糖蛋白相同的配体诱导的构象变化；（iv）意外发现三聚包膜糖蛋白单独与共受体模拟物结合可诱导与与CD4结合相同的构象变化；(v)在亚纳米分辨率下，结构证据表明，一种新的、激活的HIV中间状态，在这种状态下，病毒刺突的高度保守的内部成分暴露出来，为设计免疫原提供了一个模板，旨在激发能够阻止HIV进入的抗体。

Knowledge of the molecular structure of trimeric Env on intact viruses and delineating the mechanisms of cell-cell transmission are central to the design of effective immunogens and therapeutic agents to combat HIV/AIDS. We have continued to make significant progress towards these goals over the last year. Major advances we have made over the last year include: (i) discovery of variations in the type of virological synapses involved in mediating HIV transmission between different types of cell-cell contacts including T-cell-T-cell and T-cell-dendritic cell synapses; (ii) molecular structures of trimeric HIV-1 and SIV envelope glycoproteins from a large number of viral strains and from soluble immunogens; (iii) demonstration that soluble gp140 immunogens can display the same ligand-induced changes in conformation that are seen with native envelope glycoproteins; (iv) the unexpected finding that binding of trimeric envelope glycoproteins to a co-receptor mimic alone induces the same conformational changes as binding to CD4 and (v) structural evidence, at sub-nanometer resolution, of a novel, activated intermediate state of HIV where highly conserved, interior components of the viral spike are exposed, providing a template for the design of immunogens aimed at eliciting antibodies that could block HIV entry.