Gurczynski Stephen J, Das Subhendu, Pellett Philip E
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan, USA.
J Virol. 2014 Feb;88(4):2168-82. doi: 10.1128/JVI.02704-13. Epub 2013 Dec 11.
Human cytomegalovirus (HCMV) employs numerous strategies to combat, subvert, or co-opt host immunity. One evolutionary strategy for this involves capture of a host gene and then its successive duplication and divergence, forming a family of genes, many of which have immunomodulatory activities. The HCMV US12 family consists of 10 tandemly arranged sequence-related genes in the unique short (US) region of the HCMV genome (US12 to US21). Each gene encodes a protein possessing seven predicted transmembrane domains, patches of sequence similarity with cellular G-protein-coupled receptors, and the Bax inhibitor 1 family of antiapoptotic proteins. We show that one member, US17, plays an important role during virion maturation. Microarray analysis of cells infected with a recombinant HCMV isolate with a US17 deletion (the ΔUS17 mutant virus) revealed blunted host innate and interferon responses at early times after infection (12 h postinfection [hpi]), a pattern opposite that previously seen in the absence of the immunomodulatory tegument protein pp65 (pUL83). Although the ΔUS17 mutant virus produced numbers of infectious particles in fibroblasts equal to the numbers produced by the parental virus, it produced >3-fold more genome-containing noninfectious viral particles and delivered increased amounts of pp65 to newly infected cells. These results suggest that US17 has evolved to control virion composition, to elicit an appropriately balanced host immune response. At later time points (96 hpi), ΔUS17 mutant-infected cells displayed aberrant expression of several host endoplasmic reticulum stress response genes and chaperones, some of which are important for the final stages of virion assembly and egress. Our results suggest that US17 modulates host pathways to enable production of virions that elicit an appropriately balanced host immune response.
人巨细胞病毒(HCMV)采用多种策略来对抗、破坏或利用宿主免疫。其一种进化策略是捕获一个宿主基因,然后对其进行连续复制和分化,形成一个基因家族,其中许多基因具有免疫调节活性。HCMV US12基因家族由HCMV基因组独特短区(US)中的10个串联排列的序列相关基因组成(US12至US21)。每个基因编码一种蛋白质,该蛋白质具有7个预测的跨膜结构域、与细胞G蛋白偶联受体的序列相似区域,以及抗凋亡蛋白Bax抑制剂1家族。我们发现其中一个成员US17在病毒粒子成熟过程中起重要作用。对感染了缺失US17的重组HCMV分离株(ΔUS17突变病毒)的细胞进行微阵列分析显示,在感染后早期(感染后12小时[hpi]),宿主先天免疫和干扰素反应减弱,这种模式与之前在缺乏免疫调节性包膜蛋白pp65(pUL83)时观察到的相反。尽管ΔUS17突变病毒在成纤维细胞中产生的感染性粒子数量与亲本病毒产生的数量相等,但它产生的含基因组的非感染性病毒粒子数量多出3倍以上,并向新感染的细胞传递了更多的pp65。这些结果表明,US17已经进化到可以控制病毒粒子的组成,以引发适当平衡的宿主免疫反应。在后期时间点(96 hpi),感染ΔUS17突变体的细胞显示出几种宿主内质网应激反应基因和伴侣蛋白的异常表达,其中一些对病毒粒子组装和释放的最后阶段很重要。我们的结果表明,US17调节宿主途径,以使产生的病毒粒子能够引发适当平衡的宿主免疫反应。