Inhibition of replication of the human cytomegalovirus through interaction with tropism-relevant envelope protein

大约50%的人感染了人类巨细胞病毒（HCMV）。感染后，病毒在机体内终生存在，无临床症状。免疫抑制可导致病毒的再激活、血液传播和最终器官表现，严重的发病率，特别是在肺部和胃肠道。血管内皮细胞（ECs）和血细胞的感染主要依赖于病毒基因UL128、UL130和UL131A。我们最近绘制了这些基因通过一个系统的突变方法，关于功能重要的带电肽簇。基于这些信息，我们现在的目标是(i)揭示EC感染的分子机制，（ii）开发针对EC感染的减毒候选疫苗株，（iii）有针对性地开发具有阻止HCMV血液传播潜力的抑制肽。首先，我们将分析各种突变如何影响病毒包膜的蛋白质组成，病毒粒子附着在ECs上以及病毒包膜与细胞膜的融合。减少EC向性但保持病毒包膜蛋白组成的突变将被合并用于疫苗开发。影响含有包膜蛋白复合物UL128-131A内相互作用的肽将进一步评估其作为潜在抗病毒药物的适用性。

About 50 % of the population is infected with the human cytomegalovirus (HCMV). Following infection the virus establishes lifelong persistence in the organism without clinical symptoms. Immunosuppression can lead to reactivation, hematogenous dissemination and eventually organ manifestation of the virus with severe morbidity particularly in lung and gastrointestinal tract. The infection of vascular endothelial cells (ECs) and blood cells depends mainly on the viral genes UL128, UL130 and UL131A. We have recently mapped these genes by a systematic mutational approach with regard to functionally important charged peptide clusters. Based on this information we now aim at (i) revealing the molecular mechanisms underlying EC infection, (ii) development of candidate vaccine strains that are attenuated regarding EC infection and (iii) targeted development of inhibitory peptides with the potential to prevent hematogenous dissemination of HCMV. First we will analyze how the various mutations affect the protein composition of the viral envelope, virion attachment to ECs and fusion of viral envelope with cellular membranes. Mutations that reduce EC tropism but maintain the protein composition of the virus envelope will be combined for vaccine development. Peptides with impact on the interaction within the UL128-131A containing envelope protein complex will be further evaluated regarding suitability as potential antiviral drugs.