The University of Arizona, Tucson, AZ, USA.
J Virol. 2013 Mar;87(6):3062-75. doi: 10.1128/JVI.02510-12. Epub 2013 Jan 2.
Human cytomegalovirus (HCMV) infects a variety of cell types in humans, resulting in a varied pathogenesis in the immunocompromised host. Endothelial cells (ECs) are considered an important target of HCMV infection that may contribute to viral pathogenesis. Although the viral determinants important for entry into ECs are well defined, the molecular determinants regulating postentry tropism in ECs are not known. We previously identified the UL133-UL138 locus encoded within the clinical strain-specific ULb' region of the HCMV genome as important for the latent infection in CD34(+) hematopoietic progenitor cells (HPCs). Interestingly, this locus, while dispensable for replication in fibroblasts, was required for efficient replication in ECs infected with the TB40E or fusion-inducing factor X (FIX) HCMV strains. ECs infected with a virus lacking the entire locus (UL133-UL138(NULL) virus) complete the immediate-early and early phases of infection but are defective for infectious progeny virus production. ECs infected with UL133-UL138(NULL) virus exhibited striking differences in the organization of intracellular membranes and in the assembly of mature virions relative to ECs infected with wild-type (WT) virus. In UL133-UL138(NULL) virus-infected ECs, Golgi stacks were disrupted, and the viral assembly compartment characteristic of HCMV infection failed to form. Further, progeny virions in UL133-UL138(NULL) virus-infected ECs inefficiently acquired the virion tegument and secondary envelope. These defects were specific to infection in ECs and not observed in fibroblasts infected with UL133-UL138(NULL) virus, suggesting an EC-specific requirement for the UL133-UL138 locus for late stages of replication. To our knowledge, the UL133-UL138 locus represents the first cell-type-dependent, postentry tropism determinant required for viral maturation.
人类巨细胞病毒（HCMV）感染人类的多种细胞类型，导致免疫功能低下宿主的发病机制多样化。内皮细胞（ECs）被认为是 HCMV 感染的重要靶标，可能有助于病毒发病机制。尽管已明确确定了进入 ECs 所需的病毒决定因素，但尚不清楚调节 ECs 后进入嗜性的分子决定因素。我们之前鉴定了 HCMV 基因组临床株特异性 ULb' 区域内的 UL133-UL138 基因座，该基因座对于 CD34(+)造血祖细胞（HPCs）中的潜伏感染很重要。有趣的是，虽然该基因座对于成纤维细胞中的复制不是必需的，但对于感染 TB40E 或融合诱导因子 X（FIX）HCMV 株的 ECs 的有效复制是必需的。缺乏整个基因座（UL133-UL138(NULL)病毒）的病毒感染的 ECs 完成了早期和早期感染阶段，但无法产生感染性后代病毒。与感染 WT 病毒的 EC 相比，感染 UL133-UL138(NULL)病毒的 EC 表现出细胞内膜组织和成熟病毒粒子组装的明显差异。在 UL133-UL138(NULL)病毒感染的 EC 中，高尔基体堆栈被破坏，并且 HCMV 感染特有的病毒组装隔室未能形成。此外，在 UL133-UL138(NULL)病毒感染的 EC 中，子代病毒粒子不能有效地获得病毒被膜和二级包膜。这些缺陷是 EC 感染特异性的，在感染 UL133-UL138(NULL)病毒的成纤维细胞中未观察到，表明 UL133-UL138 基因座是病毒复制晚期的 EC 特异性要求。据我们所知，UL133-UL138 基因座是第一个需要病毒成熟的细胞类型依赖性、后进入嗜性决定因素。
