Taylor J L, Tom P, O'Brien W J
Department of Microbiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Antiviral Res. 1998 May;38(2):95-106. doi: 10.1016/s0166-3542(98)00008-4.
Treatment of cells with combinations of human interferon-alpha (IFN-alpha) and the nucleoside analog, acyclovir (ACV), leads to the synergistic inhibition of herpes simplex virus type 1 (HSV-1) replication. We have examined the effect of these agents on the replication of HSV-1 DNA and the synthesis of early viral enzymes to understand the mechanism(s) responsible for this synergistic activity. Combination treatment with 100 IU/ml IFN-alpha and 5 microM ACV led to HSV-1 DNA levels more than 8-fold lower than in cells treated with ACV alone, while IFN-alpha treatment alone had no detectable effect on viral DNA synthesis. Steady state levels of DNA polymerase were reduced approximately 50% by IFN-alpha and 25% by ACV, but combination treatment did not decrease enzyme levels to an extent greater than the sum of these effects. In contrast, the activity of another early viral enzyme, alkaline DNase, was reduced less than 20% by IFN-alpha alone or combination treatment and was unaffected by ACV treatment. No decrease in the level of mRNA encoding either enzyme was detected in IFN-alpha-treated cells although ACV treatment reduced polymerase mRNA levels. These studies suggest that the synergistic anti-HSV activities of IFN-alpha with ACV could be mediated, in part, through some post-transcriptional mechanism induced by IFN-alpha treatment, leading to the reduction in production of viral early enzymes, especially DNA polymerase.
用人干扰素-α（IFN-α）和核苷类似物阿昔洛韦（ACV）联合处理细胞，可协同抑制单纯疱疹病毒1型（HSV-1）复制。我们研究了这些药物对HSV-1 DNA复制和早期病毒酶合成的影响，以了解导致这种协同活性的机制。用100 IU/ml IFN-α和5 microM ACV联合处理导致HSV-1 DNA水平比单独用ACV处理的细胞低8倍以上，而单独用IFN-α处理对病毒DNA合成没有可检测到的影响。IFN-α使DNA聚合酶的稳态水平降低约50%，ACV使其降低25%，但联合处理并未使酶水平降低到大于这些作用之和的程度。相比之下，另一种早期病毒酶碱性DNase的活性，单独用IFN-α处理或联合处理使其降低不到20%，且不受ACV处理的影响。在IFN-α处理的细胞中未检测到编码这两种酶的mRNA水平下降，尽管ACV处理降低了聚合酶mRNA水平。这些研究表明，IFN-α与ACV的协同抗HSV活性可能部分通过IFN-α处理诱导的某些转录后机制介导，导致病毒早期酶特别是DNA聚合酶的产生减少。
