HIV-1 PRIMARY RECEPTOR CD4 IN COMPLEX WITH A POTENT ANTIVIRAL ANTIBODY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 Ibalizumab是一种人源化的抗CD4单抗。它能有效地阻断HIV-1感染，并靶向CD4第二区域的一个表位，而不会干扰通过CD4与主要组织相容性复合体(MHC)II类分子相互作用而介导的免疫功能。我们测定了Ibalizumab Fab片段与CD_4的前两个结构域(D_1~D_2)在2.2°分辨率下的晶体结构。Ibalizumab主要通过D2的BC环(残基121-125)结合CD4，位于gp120和MHC-II结合位点的对面。与ibalizumab结合时，CD4的构象没有重大变化。单价和二价形式的ibalizumab都有效地阻断了病毒感染，这表明它不需要交联CD4来发挥抗病毒活性。虽然gp120诱导的CD4的结构重排可能很小，但对于ibalizumab的抑制，CD4的结构刚性是必不可少的。这些结果可以指导基于CD4的免疫原设计，并导致对HIV-1进入的更好理解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We have determined the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 ¿ resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.