Jardine Joseph G, Ota Takayuki, Sok Devin, Pauthner Matthias, Kulp Daniel W, Kalyuzhniy Oleksandr, Skog Patrick D, Thinnes Theresa C, Bhullar Deepika, Briney Bryan, Menis Sergey, Jones Meaghan, Kubitz Mike, Spencer Skye, Adachi Yumiko, Burton Dennis R, Schief William R, Nemazee David
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center (NAC), The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science. 2015 Jul 10;349(6244):156-61. doi: 10.1126/science.aac5894. Epub 2015 Jun 18.
A major goal of HIV-1 vaccine research is the design of immunogens capable of inducing broadly neutralizing antibodies (bnAbs) that bind to the viral envelope glycoprotein (Env). Poor binding of Env to unmutated precursors of bnAbs, including those of the VRC01 class, appears to be a major problem for bnAb induction. We engineered an immunogen that binds to VRC01-class bnAb precursors and immunized knock-in mice expressing germline-reverted VRC01 heavy chains. Induced antibodies showed characteristics of VRC01-class bnAbs, including a short CDRL3 (light-chain complementarity-determining region 3) and mutations that favored binding to near-native HIV-1 gp120 constructs. In contrast, native-like immunogens failed to activate VRC01-class precursors. The results suggest that rational epitope design can prime rare B cell precursors for affinity maturation to desired targets.
HIV-1疫苗研究的一个主要目标是设计能够诱导与病毒包膜糖蛋白（Env）结合的广泛中和抗体（bnAbs）的免疫原。Env与bnAbs未突变前体（包括VRC01类bnAbs前体）的结合不佳似乎是诱导bnAbs的一个主要问题。我们设计了一种与VRC01类bnAb前体结合的免疫原，并对表达种系回复VRC01重链的敲入小鼠进行免疫。诱导产生的抗体表现出VRC01类bnAbs的特征，包括短的CDRL3（轻链互补决定区3）以及有利于与接近天然的HIV-1 gp120构建体结合的突变。相比之下，类似天然的免疫原未能激活VRC01类前体。结果表明，合理的表位设计可以引发罕见的B细胞前体进行亲和力成熟，以靶向所需目标。
