Interferons regulate the phenotype of wild-type and mutant herpes simplex viruses in vivo.
Interferons regulate the phenotype of wild-type and mutant herpes simplex viruses in vivo.
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DOI：
10.1084/jem.189.4.663
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发表时间：
1999-02-15
期刊：
影响因子：
--
通讯作者：
Virgin HW
中科院分区：
文献类型：
--
作者：
Leib DA;Harrison TE;Laslo KM;Machalek MA;Moorman NJ;Virgin HW
单纯疱疹病毒（HSV）的神经衰减机制已被确定以前的研究在培养细胞中的突变病毒。检验了宿主基因中的无效突变可以覆盖某些病毒基因中无效突变的减毒表型的假设。突变体如感染细胞蛋白（ICP）0、胸苷激酶、核糖核苷酸还原酶、病毒体宿主关闭和ICP 34.5中的突变体在培养和体内非分裂细胞中复制的能力降低。角膜接种后1-7天，在I型IFN（IFN-α/βR）、II型IFN（IFN-γR）以及I型和II型IFN（IFN-α/β/γR）的干扰素受体（IFNR）无效突变（−/−）的小鼠中，检查了这些病毒在眼睛和三叉神经节中的复制。IFN-γR−/−小鼠眼睛和神经节中的病毒滴度与同类对照无显著差异。然而，在IFN-α/βR−/−或IFN-α/β/γR−/−小鼠中，所有突变体的生长，包括那些在细胞培养中生长显著受损的突变体，在眼睛和三叉神经节中的生长增加了1,000倍。对于所有病毒，在IFN-α/βR−/−和IFN-α/β/γR−/−小鼠中睑缘炎和感染的临床体征明显，但对照组小鼠则不明显。此外，IFN显示出显著减少了完整但未划痕的角膜的生产性感染和传播。特别引人注目的是，在IFN-α/βR−/−小鼠中恢复了接近正常的三叉神经节复制和ICP34.5突变体的神经毒力。这些数据表明，IFN在限制突变型和野生型HSV在角膜和神经系统中的复制中起主要作用。此外，ICP34.5的体内靶点可能是宿主IFN应答。这些实验证明了宿主因子在体内定义某些HSV突变体的表型中的未知作用。因此，突变病毒的表型不能仅根据细胞培养研究来解释，而必须在可能定义体内表型的宿主因素的背景下仔细考虑。
Mechanisms responsible for neuroattenuation of herpes simplex virus (HSV) have been defined previously by studies of mutant viruses in cultured cells. The hypothesis that null mutations in host genes can override the attenuated phenotype of null mutations in certain viral genes was tested. Mutants such as those in infected cell protein (ICP) 0, thymidine kinase, ribonucleotide reductase, virion host shutoff, and ICP34.5 are reduced in their capacity to replicate in nondividing cells in culture and in vivo. The replication of these viruses was examined in eyes and trigeminal ganglia for 1–7 d after corneal inoculation in mice with null mutations (−/−) in interferon receptors (IFNR) for type I IFNs (IFN-α/βR), type II IFN (IFN-γR), and both type I and type II IFNs (IFN-α/β/γR). Viral titers in eyes and ganglia of IFN-γR−/− mice were not significantly different from congenic controls. However, in IFN-α/βR−/− or IFN-α/β/γR−/− mice, growth of all mutants, including those with significantly impaired growth in cell culture, was enhanced by up to 1,000-fold in eyes and trigeminal ganglia. Blepharitis and clinical signs of infection were evident in IFN-α/βR−/− and IFN-α/β/γR−/− but not control mice for all viruses. Also, IFNs were shown to significantly reduce productive infection of, and spread from intact, but not scarified, corneas. Particularly striking was restoration of near-normal trigeminal ganglion replication and neurovirulence of an ICP34.5 mutant in IFN-α/βR−/− mice. These data show that IFNs play a major role in limiting mutant and wild-type HSV replication in the cornea and in the nervous system. In addition, the in vivo target of ICP34.5 may be host IFN responses. These experiments demonstrate an unsuspected role for host factors in defining the phenotypes of some HSV mutants in vivo. The phenotypes of mutant viruses therefore cannot be interpreted based solely upon studies in cell culture but must be considered carefully in the context of host factors that may define the in vivo phenotype.
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DOI：
10.1073/pnas.92.23.10516
发表时间：
1995-11-07
影响因子：
11.1
作者：
CHOU, J;CHEN, JJ;ROIZMAN, B
通讯作者：
ROIZMAN, B
影响因子：
11.4
作者：
EVERETT, RD
通讯作者：
EVERETT, RD
影响因子：
15.3
作者：
Goldsmith, K;Chen, W;Johnson, DC;Hendricks, RL
通讯作者：
Hendricks, RL
影响因子：
3.7
作者：
Halford, WP;Veress, LA;Carr, DJJ
通讯作者：
Carr, DJJ
影响因子：
5.4
作者：
GOLDSTEIN, DJ;WELLER, SK
通讯作者：
WELLER, SK