Manuelidis L, Fritch W
Yale Medical School, New Haven, Connecticut 06510, USA.
Virology. 1996 Feb 1;216(1):46-59. doi: 10.1006/viro.1996.0033.
The relationship between viral titer and host responses was evaluated in Creutzfeldt-Jakob Disease (CJD). Rapid clearing of 97% of the virus from hamster brain occurred within 5 days, and residual virus was dispersed equally to both hemispheres. Exponential replication began only after a long eclipse phase of approximately 30 days, and by 100 days showed an > 3 log increase in titer. However, from 100 to 135 days, titers were restricted to plateau levels of approximately 10(8)/g. In comparison, previous studies show no appreciable eclipse phase and > or = 100-fold higher brain titers in hamster scrapie. Our calculations also revealed an effective doubling time (ti) of 7.6 days in CJD and a markedly different ti of approximately 3 days in scrapie. Thus different initiation and replication programs are encoded by each of these strains. The most pertinent host molecular responses included early astrocytic activity by 54 days, unaccompanied by morphological or behavioral changes. Changes in host PrP were minimal until 87 days when titers were already 2 x 10(7)/g. In the next 20 days 60% of brain PrP became resistant to limited proteolysis but total PrP did not increase. These fulminant PrP changes preceded viral arrest and subsequent spongiform degeneration. Because these and other data are not consistent with PrP itself being the infectious agent, we discuss a model in which progressive PrP and glial activation are part of a final host strategy to contain a virus that is innocuous at low titers. This strategy is flawed because PrP is an independent provocateur of self-destruction in the brain. However, in the periphery this strategy may eliminate rare infected cells.
在克雅氏病（CJD）中评估了病毒滴度与宿主反应之间的关系。97%的病毒在5天内从仓鼠脑中快速清除，残余病毒均匀分布于两个半球。指数复制仅在约30天的长潜伏期后开始，到100天时滴度增加超过3个对数。然而，从100天到135天，滴度限制在约10(8)/g的平台水平。相比之下，先前的研究表明仓鼠瘙痒病没有明显的潜伏期，脑滴度高出100倍及以上。我们的计算还显示，CJD的有效倍增时间（ti）为7.6天，而瘙痒病的ti明显不同，约为3天。因此，这些毒株各自编码不同的起始和复制程序。最相关的宿主分子反应包括54天时早期星形细胞活动，且无形态或行为变化。宿主PrP的变化在87天之前最小，此时滴度已达2×10(7)/g。在接下来的20天里，60%的脑PrP对有限蛋白酶解产生抗性，但总PrP没有增加。这些迅速的PrP变化先于病毒停滞和随后的海绵状变性。由于这些及其他数据与PrP本身作为感染因子不一致，我们讨论了一个模型，其中渐进性PrP和胶质细胞激活是宿主最终控制低滴度无害病毒策略的一部分。该策略存在缺陷，因为PrP是大脑自我毁灭的独立诱因。然而，在外周，该策略可能消除罕见的感染细胞。
