抗α-半乳糖基天然抗体介导的人血清中逆转录病毒失活的新机制。
A novel mechanism of retrovirus inactivation in human serum mediated by anti-alpha-galactosyl natural antibody.
作者信息
Rother R P, Fodor W L, Springhorn J P, Birks C W, Setter E, Sandrin M S, Squinto S P, Rollins S A
机构信息
Department of Molecular Development, Alexion Pharmaceuticals Inc., New Haven, Connecticut 06511, USA.
出版信息
J Exp Med. 1995 Nov 1;182(5):1345-55. doi: 10.1084/jem.182.5.1345.
Type C retroviruses endogenous to various nonprimate species can infect human cells in vitro, yet the transmission of these viruses to humans is restricted. This has been attributed to direct binding of the complement component C1q to the viral envelope protein p15E, which leads to classical pathway-mediated virolysis in human serum. Here we report a novel mechanism of complement-mediated type C retrovirus inactivation that is initiated by the binding of "natural antibody" [Ab] (anti-alpha-galactosyl Ab) to the carbohydrate epitope Gal alpha 1-3Gal beta 1-4GlcNAc-R expressed on the retroviral envelope. Complement-mediated inactivation of amphotropic retroviral particles was found to be restricted to human and other Old World primate sera, which parallels the presence of anti-alpha-galactosyl natural Ab. Blockade or depletion of anti-alpha-galactosyl Ab in human serum prevented inactivation of both amphotropic and ecotropic murine retroviruses. Similarly, retrovirus was not killed by New World primate serum except in the presence of exogenous anti-alpha-galactosyl Ab. Enzyme-linked immunosorbent assays revealed that the alpha-galactosyl epitope was expressed on the surface of amphotropic and ecotropic retroviruses, and Western blot analysis further localized this epitope to the retroviral envelope glycoprotein gp70. Finally, down-regulation of this epitope on the surface of murine retroviral particle producer cells rendered them, as well as the particles liberated from these cells, resistant to inactivation by human serum complement. Our data suggest that anti-alpha-galactosyl Ab may provide a barrier for the horizontal transmission of retrovirus from species that express the alpha-galactosyl epitope to humans and to other Old World primates. Further, these data provide a mechanism for the generation of complement-resistant retroviral vectors for in vivo gene therapy applications where exposure to human complement is unavoidable.
各种非灵长类物种内源性的C型逆转录病毒可在体外感染人类细胞，但这些病毒向人类的传播受到限制。这归因于补体成分C1q与病毒包膜蛋白p15E的直接结合，从而导致人血清中经典途径介导的病毒溶解。在此，我们报告一种补体介导的C型逆转录病毒失活的新机制，该机制由“天然抗体”[Ab]（抗α-半乳糖基抗体）与逆转录病毒包膜上表达的碳水化合物表位Galα1-3Galβ1-4GlcNAc-R结合引发。发现补体介导的双嗜性逆转录病毒颗粒失活仅限于人类和其他旧世界灵长类动物的血清，这与抗α-半乳糖基天然抗体的存在情况相似。人血清中抗α-半乳糖基抗体的阻断或消耗可防止双嗜性和嗜亲性鼠逆转录病毒的失活。同样，除了存在外源性抗α-半乳糖基抗体外，新世界灵长类动物血清不会杀死逆转录病毒。酶联免疫吸附测定显示，α-半乳糖基表位在双嗜性和嗜亲性逆转录病毒表面表达，蛋白质印迹分析进一步将该表位定位到逆转录病毒包膜糖蛋白gp70。最后，鼠逆转录病毒颗粒产生细胞表面该表位的下调使它们以及从这些细胞释放的颗粒对人血清补体的失活具有抗性。我们的数据表明，抗α-半乳糖基抗体可能为逆转录病毒从表达α-半乳糖基表位的物种向人类和其他旧世界灵长类动物的水平传播提供障碍。此外，这些数据为在体内基因治疗应用中产生抗补体的逆转录病毒载体提供了一种机制，在这些应用中不可避免地会接触到人补体。
Zotero 插件