Ziaie Z, Brinker J M, Kefalides N A
Connective Tissue Research Institute, University of Pennsylvania, Philadelphia.
Lab Invest. 1994 Jan;70(1):29-38.
Patients treated with lithium salts for manic depression had a lower incidence of herpes simplex infections. Initial studies in our laboratory demonstrated that addition of LiCl in cultures of human endothelial cells infected with herpes simplex virus suppressed viral replication and allowed synthesis of host proteins.
Based on the above observations, we decided to study the optimal condition for the lithium effect and determine the process of inhibition of viral replication. Endothelial cell cultures infected with herpes simplex virus-1 were exposed to LiCl at various times postinfection. The levels of host and viral mRNAs were measured by Northern and slot blot hybridization. The pattern of protein synthesis was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot and replication was assessed by plaque assay.
LiCl inhibited virus replication in a dose- and time-dependent manner as was reflected in the sharp decrease or absence of infectious virus production. The condition for optimal effects of LiCl were the addition of the salt between 0-3 hours postinfection, and at a concentration of 30 mM. LiCl suppressed the synthesis of viral polypeptides, whereas the synthesis of host proteins was maintained. Similar results were observed with phosphonoacetic acid, an inhibitor of viral DNA polymerase. NaCl, at the same concentration as LiCl, did not prevent the virus-induced inhibition of host cell protein synthesis. The level of host mRNA for fibronectin, thrombospondin, collagen type IV, actin, and plasminogen activator inhibitor-1 were maintained in the presence of LiCl. mRNAs for viral proteins, ICP-4 and DNA polymerase were nearly undetectable when LiCl was added with the virus (0 time postinfection).
The data indicate that LiCl treatment results in suppression of herpes virus mRNAs, i.e., mRNAs for ICP-4 and DNA polymerase, thereby inhibiting replication. On the other hand, the levels of host mRNAs are maintained to varying degrees depending on the message. The data suggest that a very early step in the process of viral replication is affected by LiCl, since the drug is maximally effective when added with the virus.
接受锂盐治疗躁狂抑郁症的患者单纯疱疹感染的发生率较低。我们实验室的初步研究表明，在感染单纯疱疹病毒的人内皮细胞培养物中添加氯化锂可抑制病毒复制，并允许宿主蛋白的合成。
基于上述观察结果，我们决定研究锂效应的最佳条件，并确定病毒复制的抑制过程。感染单纯疱疹病毒1的内皮细胞培养物在感染后的不同时间暴露于氯化锂。通过Northern和狭缝印迹杂交测量宿主和病毒mRNA的水平。通过十二烷基硫酸钠-聚丙烯酰胺凝胶电泳和免疫印迹分析蛋白质合成模式，并通过噬斑测定评估复制情况。
氯化锂以剂量和时间依赖性方式抑制病毒复制，这反映在感染性病毒产生的急剧减少或不存在上。氯化锂最佳效果的条件是在感染后0-3小时添加盐，浓度为30 mM。氯化锂抑制病毒多肽的合成，而宿主蛋白的合成得以维持。用病毒DNA聚合酶抑制剂膦甲酸观察到类似结果。与氯化锂浓度相同的氯化钠不能阻止病毒诱导的宿主细胞蛋白合成抑制。在氯化锂存在下，纤连蛋白、血小板反应蛋白、IV型胶原、肌动蛋白和纤溶酶原激活物抑制剂-1的宿主mRNA水平得以维持。当与病毒一起添加氯化锂（感染后0小时）时，病毒蛋白ICP-4和DNA聚合酶的mRNA几乎检测不到。
数据表明，氯化锂处理导致单纯疱疹病毒mRNA（即ICP-4和DNA聚合酶的mRNA）的抑制，从而抑制复制。另一方面，宿主mRNA的水平根据信息在不同程度上得以维持。数据表明，病毒复制过程中的一个非常早期的步骤受到氯化锂的影响，因为该药物在与病毒一起添加时效果最佳。
