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。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 Ibalizumab是一种人源化抗CD 4单克隆抗体。它有效地阻断HIV-1感染并靶向CD 4第二结构域中的表位，而不干扰由CD 4与主要组织相容性复合体（MHC）II类分子相互作用介导的免疫功能。我们以2.2分辨率测定了ibalizumab Fab片段与CD 4前两个结构域（D1-D2）复合物的晶体结构。Ibalizumab主要通过D2的BC环（残基121-125）抓住CD 4，位于gp 120和MHC-II结合位点的相对侧。与ibalizumab结合时，CD 4无重大构象变化。ibalizumab的单价和二价形式都能有效阻断病毒感染，这表明它不需要交联CD 4就能发挥抗病毒活性。虽然gp 120诱导的CD 4结构重排可能很小，但CD 4结构刚性对ibalizumab抑制作用不利。这些结果可以指导基于CD 4的免疫原设计，并导致更好地理解HIV-1进入。

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.