An Endothelial Cell-Specific Requirement for the UL133-UL138 Locus of Human Cytomegalovirus for Efficient Virus Maturation
An Endothelial Cell-Specific Requirement for the UL133-UL138 Locus of Human Cytomegalovirus for Efficient Virus Maturation
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DOI：
10.1128/jvi.02510-12
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发表时间：
2013-03-01
影响因子：
5.4
通讯作者：
Goodrum, Felicia
中科院分区：
文献类型：
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作者：
Bughio, Farah;Elliott, David A.;Goodrum, Felicia
人巨细胞病毒（HCMV）感染人体多种细胞类型，导致免疫受损宿主的发病机制不同。内皮细胞（EC）被认为是HCMV感染的重要靶点，可能有助于病毒的发病机制。虽然病毒进入内皮细胞的重要决定因素是明确的，但调节内皮细胞中的后向性的分子决定因素尚不清楚。我们先前鉴定了在HCMV基因组的临床株特异性ULb'区域内编码的UL 133-UL 138基因座对于CD 34（+）造血祖细胞（HPC）中的潜伏感染是重要的。有趣的是，这个位点，虽然在成纤维细胞中复制，需要在感染TB 40 E或融合诱导因子X（FIX）HCMV株的EC中有效复制。用缺乏整个基因座的病毒（UL 133-UL 138（NULL）病毒）感染的EC完成感染的立即早期和早期阶段，但对于感染性子代病毒产生是有缺陷的。感染UL 133-UL 138（NULL）病毒的EC相对于感染野生型（WT）病毒的EC在细胞内膜的组织和成熟病毒体的组装方面表现出显著差异。在UL 133-UL 138（NULL）病毒感染的EC中，高尔基体被破坏，并且HCMV感染的病毒组装区室特征未能形成。此外，UL 133-UL 138（NULL）病毒感染的EC中的子代病毒体不能有效地获得病毒体被膜和次级包膜。这些缺陷对EC中的感染是特异性的，而在用UL 133-UL 138（NULL）病毒感染的成纤维细胞中未观察到，这表明在复制的晚期阶段对UL 133-UL 138基因座的EC特异性要求。据我们所知，UL 133-UL 138基因座代表了病毒成熟所需的第一个细胞类型依赖性、感染后嗜性决定因子。
Human cytomegalovirus (HCMV) infects a variety of cell types in humans, resulting in a varied pathogenesis in the immuno-compromised 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.