Sliepen Kwinten, van Montfort Thijs, Melchers Mark, Isik Gözde, Sanders Rogier W
From the Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and.
From the Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and Weill Medical College of Cornell University, New York, New York 10065
J Biol Chem. 2015 Mar 20;290(12):7436-42. doi: 10.1074/jbc.M114.620534. Epub 2015 Jan 29.
Many therapeutic proteins and protein subunit vaccines contain heterologous trimerization domains, such as the widely used GCN4-based isoleucine zipper (IZ) and the T4 bacteriophage fibritin foldon (Fd) trimerization domains. We found that these domains induced potent anti-IZ or anti-Fd antibody responses in animals when fused to an HIV-1 envelope glycoprotein (Env) immunogen. To dampen IZ-induced responses, we constructed an IZ domain containing four N-linked glycans (IZN4) to shield the underlying protein surface. When fused to two different vaccine antigens, HIV-1 Env and influenza hemagglutinin (HA), IZN4 strongly reduced the antibody responses against the IZ, but did not affect the antibody titers against Env or HA. Silencing of immunogenic multimerization domains with glycans might be relevant for therapeutic proteins and protein vaccines.
许多治疗性蛋白质和蛋白质亚基疫苗都含有异源三聚化结构域，比如广泛使用的基于GCN4的异亮氨酸拉链（IZ）和T4噬菌体纤维蛋白折叠结构域（Fd）三聚化结构域。我们发现，当这些结构域与HIV-1包膜糖蛋白（Env）免疫原融合时，会在动物体内诱导产生强效的抗IZ或抗Fd抗体反应。为了减弱IZ诱导的反应，我们构建了一个含有四个N-连接聚糖的IZ结构域（IZN4），以屏蔽其下方的蛋白质表面。当与两种不同的疫苗抗原HIV-1 Env和流感血凝素（HA）融合时，IZN4强烈降低了针对IZ的抗体反应，但不影响针对Env或HA的抗体滴度。用聚糖沉默免疫原性多聚化结构域可能与治疗性蛋白质和蛋白质疫苗有关。
