Olson Annabel T, Child Stephanie J, Geballe Adam P
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, 1100 Fairview Ave N Seattle, P.O. Box 19024, Seattle, WA 98109, USA.
Departments of Microbiology, University of Washington, Seattle, WA 98195, USA.
Pathogens. 2022 Jul 12;11(7):790. doi: 10.3390/pathogens11070790.
Decades of research on vaccinia virus (VACV) have provided a wealth of insights and tools that have proven to be invaluable in a broad range of studies of molecular virology and pathogenesis. Among the challenges that viruses face are intrinsic host cellular defenses, such as the protein kinase R pathway, which shuts off protein synthesis in response to the dsRNA that accumulates during replication of many viruses. Activation of PKR results in phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), inhibition of protein synthesis, and limited viral replication. VACV encodes two well-characterized antagonists, E3L and K3L, that can block the PKR pathway and thus enable the virus to replicate efficiently. The use of VACV with a deletion of the dominant factor, E3L, enabled the initial identification of PKR antagonists encoded by human cytomegalovirus (HCMV), a prevalent and medically important virus. Understanding the molecular mechanisms of E3L and K3L function facilitated the dissection of the domains, species-specificity, and evolutionary potential of PKR antagonists encoded by human and nonhuman CMVs. While remaining cognizant of the substantial differences in the molecular virology and replication strategies of VACV and CMVs, this review illustrates how VACV can provide a valuable guide for the study of other experimentally less tractable viruses.
数十年来对痘苗病毒（VACV）的研究提供了丰富的见解和工具，这些已被证明在广泛的分子病毒学和发病机制研究中具有极高价值。病毒面临的挑战之一是宿主细胞的固有防御，例如蛋白激酶R途径，它会在许多病毒复制过程中积累的双链RNA的作用下关闭蛋白质合成。PKR的激活会导致真核起始因子2（eIF2α）的α亚基磷酸化，抑制蛋白质合成，并限制病毒复制。VACV编码两种特征明确的拮抗剂E3L和K3L，它们可以阻断PKR途径，从而使病毒能够高效复制。使用缺失主要因子E3L的VACV，使得最初能够鉴定出人类巨细胞病毒（HCMV，一种普遍且具有医学重要性的病毒）编码的PKR拮抗剂。了解E3L和K３L的功能分子机制有助于剖析人类和非人巨细胞病毒编码的PKR拮抗剂的结构域、物种特异性和进化潜力。尽管认识到VACV与巨细胞病毒在分子病毒学和复制策略上存在重大差异，但本综述阐述了VACV如何为研究其他实验上较难处理的病毒提供有价值的指导。
