Stabilization of HIV-1 Envelope in the CD4-bound Conformation through Specific Cross-linking of a CD4 Mimetic
Stabilization of HIV-1 Envelope in the CD4-bound Conformation through Specific Cross-linking of a CD4 Mimetic
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DOI：
10.1074/jbc.m111.232272
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发表时间：
2011-06-17
影响因子：
4.8
通讯作者：
Martin, Loic
中科院分区：
文献类型：
--
作者：
Martin, Gregoire;Burke, Brian;Martin, Loic
CD 4与gp 120的结合导致HIV共受体CCR 5和CD 4诱导的（CD 4 i）抗体识别的高度保守区域暴露。显示共价gp 120-CD 4复合物在猴中引发CD 4 i抗体应答，这与HIV病毒感染的控制相关（DeVico，A.，福茨，T.，刘易斯，G. K.，加洛河C.的方法，戈弗雷，K.，Charurat，M.，哈里斯岛，加尔明湖，和R.等人（2007）Proc.Natl. Acad. Sci.联合S. A. 104，17477-17482）。由于应避免在疫苗制剂中包含CD 4，由于潜在的自身免疫反应，我们设计了免疫原性差且不诱导抗CD 4抗体的小尺寸CD 4模拟物（miniCD 4）。我们通过定点偶联反应在这种工程化的miniCD 4和gp 120或gp 140之间形成共价复合物。这些复合物被CD 4 i抗体以及HIV共受体CCR 5识别。此外，它们在兔中引发CD 4 i抗体应答，因此代表了模拟重要的HIV融合中间体的潜在疫苗候选物，而没有自身免疫危害。
CD4 binding on gp120 leads to the exposure of highly conserved regions recognized by the HIV co-receptor CCR5 and by CD4-induced (CD4i) antibodies. A covalent gp120-CD4 complex was shown to elicit CD4i antibody responses in monkeys, which was correlated with control of the HIV virus infection (DeVico, A., Fouts, T., Lewis, G. K., Gallo, R. C., Godfrey, K., Charurat, M., Harris, I., Galmin, L., and Pal, R. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 17477-17482). Because the inclusion of CD4 in a vaccine formulation should be avoided, due to potential autoimmune reactions, we engineered small sized CD4 mimetics (miniCD4s) that are poorly immunogenic and do not induce anti-CD4 antibodies. We made covalent complexes between such an engineered miniCD4 and gp120 or gp140, through a site-directed coupling reaction. These complexes were recognized by CD4i antibodies as well as by the HIV co-receptor CCR5. In addition, they elicit CD4i antibody responses in rabbits and therefore represent potential vaccine candidates that mimic an important HIV fusion intermediate, without autoimmune hazard.