Medina-Ramírez Max, Garces Fernando, Escolano Amelia, Skog Patrick, de Taeye Steven W, Del Moral-Sanchez Ivan, McGuire Andrew T, Yasmeen Anila, Behrens Anna-Janina, Ozorowski Gabriel, van den Kerkhof Tom L G M, Freund Natalia T, Dosenovic Pia, Hua Yuanzi, Gitlin Alexander D, Cupo Albert, van der Woude Patricia, Golabek Michael, Sliepen Kwinten, Blane Tanya, Kootstra Neeltje, van Breemen Mariëlle J, Pritchard Laura K, Stanfield Robyn L, Crispin Max, Ward Andrew B, Stamatatos Leonidas, Klasse Per Johan, Moore John P, Nemazee David, Nussenzweig Michel C, Wilson Ian A, Sanders Rogier W
Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Department of Integrative Structural and Computational Biology, Scripps CHAVI-ID, IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla, CA.
J Exp Med. 2017 Sep 4;214(9):2573-2590. doi: 10.1084/jem.20161160. Epub 2017 Aug 28.
Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.
通过HIV-1包膜糖蛋白免疫原诱导广泛中和抗体（bNAbs）将是朝着有效疫苗迈出的重要一步。这一过程中的关键步骤是激活表达种系（gl）抗体前体的幼稚B细胞，这些前体有可能进化为bNAbs。在此，我们对BG505 SOSIP.664糖蛋白进行了重新设计，以结合靶向三聚体顶端或CD4结合位点的bNAbs的gl前体。所得的BG505 SOSIP.v4.1-GT1三聚体在体外可结合多种bNAb gl前体。在表达gl-VRC01或gl-PGT121的敲入小鼠中进行的免疫实验表明，这种三聚体在体内可激活B细胞，导致血清中分泌特异性抗体。与中和抗体35O22和9H+109L形成复合物的靶向gl三聚体的晶体结构在3.2 Å分辨率下揭示了一种天然样构象，并成功纳入了与多种gl-bNAb前体结合相关的设计特征。
