Human Cytomegalovirus Entry Glycoprotein Complexes

描述（由申请人提供）：该提案代表了Jardetzky实验室在HCMV进入糖蛋白方面的新研究方向，该实验室此前曾广泛致力于了解eb病毒（EBV）进入靶细胞并开发新的治疗干预方法。HCMV进入上皮细胞和内皮细胞需要形成由gH、gL、UL128、UL130和UL131蛋白组成的五聚体病毒糖蛋白复合物（gHgL/UL128-131）。这种五聚体复合物是EBV gHgL/gp42复合物的功能类似物，其靶向EBV感染B细胞。HCMV gHgL还与氧化石墨烯蛋白组装成三聚体复合物，具有更广泛的功能作用，影响病毒进入成纤维细胞、上皮细胞和内皮细胞。Jardetzky实验室对EBV gHgL和gp42复合物进行了广泛的晶体学和功能研究，并证明EBV感染可以用gp42衍生的高亲和力肽抑制剂阻断。我们现在建议对HCMV gHgL、gHgL/gO和gHgL/UL128-131复合物进行类似的研究，并研究HCMV gHgL复合物与中和抗体的相互作用。这些研究将进一步加深我们对疱疹病毒进入机制的理解，并可能为开发HCMV进入抑制剂或gHgL亚单位疫苗开辟新的途径。

DESCRIPTION (provided by applicant): This proposal represents a new research direction on HCMV entry glycoproteins for the Jardetzky Laboratory, which has previously had extensive prior effort focusing on understanding Epstein-Barr virus (EBV) entry into target cells and on developing novel approaches to therapeutic intervention. The entry of HCMV into epithelial and endothelial cells requires the formation of a pentameric viral glycoprotein complex comprised of the gH, gL, UL128, UL130, and UL131 proteins (gHgL/UL128-131). This pentameric complex is a functional analog of the EBV gHgL/gp42 complex, which targets EBV to infect B cells. HCMV gHgL also assembles into a trimeric complex with the gO protein, which has a broader functional role, affecting virus entry into fibroblasts, epithelial cells and endothelial cells. Th Jardetzky Laboratory has conducted extensive crystallographic and functional studies of the EBV gHgL and gp42 complexes and demonstrated that EBV infection can be blocked with a gp42-derived high affinity peptide inhibitor. We now propose to conduct similar studies of the HCMV gHgL, gHgL/gO and gHgL/UL128-131 complexes, as well as examine the interaction of HCMV gHgL complexes with neutralizing antibodies. These studies will further our understanding of herpesvirus entry mechanisms and may lead to new routes to developing HCMV entry inhibitors or gHgL subunit vaccines.