Fawl R L, Roizman B
Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, Illinois 60637.
J Virol. 1993 Dec;67(12):7025-31. doi: 10.1128/JVI.67.12.7025-7031.1993.
Herpes simplex viruses maintained in a latent state in sensory neurons in mice do not reactivate spontaneously, and therefore the factors or procedures which cause the virus to reactivate serve as a clue to the mechanisms by which the virus is maintained in a latent state. We report that cadmium sulfate induces latent virus to reactivate in 75 to 100% of mice tested. The following specific findings are reported. (i) The highest frequency of induction was observed after two to four daily administrations of 100 micrograms of cadmium sulfate. (ii) Zinc, copper, manganese, or nickel sulfate administered in equimolar amounts under the same regimen did not induce viral reactivation; however, zinc sulfate in molar ratios 25-fold greater than those of cadmium induced viral replication in 2 of 16 ganglia tested. (iii) Administration of zinc, nickel, or manganese prior to the cadmium sulfate reduced the incidence of ganglia containing infectious virus. (iv) Administration of cadmium daily during the first week after infection and at 2-day intervals to 13 days after infection resulted in the recovery from ganglia of infectious virus in titers 10- to 100-fold higher than those obtained from animals given saline. Moreover, infectious virus was recovered as late as 11 days after infection compared with 6 days in mice administered saline. (v) Administration of cadmium immediately after infection or repeatedly after establishment of latency did not exhaust the latent virus harbored by sensory neurons, inasmuch as the fraction of ganglia of mice administered cadmium and yielding infectious virus was similar to that observed in mice treated with saline. We conclude that induction of cadmium tolerance precludes reactivation of latent virus. If the induction of metallothionein genes was the sole factor required to cause reactivation of latent virus, it would have been expected that all metals which induce metallothioneins would also induce reactivation, which was not observed. The results therefore raise the possibility that in addition to inducing the metallothionein genes, cadmium inactivates the factors which maintain the virus in latent state.
单纯疱疹病毒在小鼠感觉神经元中处于潜伏状态时不会自发激活，因此，导致病毒激活的因素或过程可作为了解病毒维持潜伏状态机制的线索。我们报告称，硫酸镉可使75%至100%受试小鼠体内的潜伏病毒激活。以下是具体研究结果：(i) 每天给予100微克硫酸镉，连续两至四天后，观察到最高的激活频率。(ii) 在相同给药方案下，等摩尔量的硫酸锌、硫酸铜、硫酸锰或硫酸镍不会诱导病毒激活；然而，硫酸锌与镉的摩尔比为25倍时，在16个受试神经节中有2个诱导了病毒复制。(iii) 在硫酸镉给药前给予锌、镍或锰，可降低含有感染性病毒的神经节发生率。(iv) 在感染后第一周每天给予镉，并在感染后2天间隔给药至13天，从神经节中回收的感染性病毒滴度比给予生理盐水的动物高10至100倍。此外，与给予生理盐水的小鼠在感染后6天相比，感染后11天仍可回收感染性病毒。(v) 感染后立即给予镉或在潜伏状态建立后反复给药，并不会耗尽感觉神经元中潜伏的病毒，因为给予镉并产生感染性病毒的小鼠神经节比例与给予生理盐水的小鼠相似。我们得出结论，诱导镉耐受性可防止潜伏病毒激活。如果诱导金属硫蛋白基因是导致潜伏病毒激活的唯一因素，那么预计所有诱导金属硫蛋白的金属也会诱导激活，但实际并非如此。因此，这些结果增加了一种可能性，即除了诱导金属硫蛋白基因外，镉还会使维持病毒潜伏状态的因素失活。
