Loveys D A, Kulkarni S, Atreya P L
Laboratory of Pediatric and Respiratory Viral Diseases, DVP/CBER, Food and Drug Administration, Bethesda, MD 20892, USA.
Virology. 2000 Jun 5;271(2):390-400. doi: 10.1006/viro.2000.0290.
The contributions of type I interferons (IFNs) to the in vitro attenuation of three temperature-sensitive (Ts) subgroup A and one subgroup B deletion mutant RSV strains were evaluated. The ability of these vaccine viruses to induce IFNs at their permissive and restrictive temperatures and their sensitivity to the antiviral effects of exogenous I IFNs were tested in human lung epithelial A549 cells. Our results show that the highly attenuated and immunogenic subgroup A vaccine strain Ts1C produced higher levels of IFN-beta than its parent RSS-2 or two related strains, Ts1A and Ts1B, at their permissive temperature. Growth of RSV-infected A549 cultures at restrictive temperatures or prior UV inactivation of the virus abolished the observed induction of IFN-beta, suggesting a strict requirement of viral replication for cellular IFN induction. The enhanced induction of IFN-beta by the highly immunogenic Ts1C at permissive temperature may be an advantageous characteristic of a live intranasal vaccine candidate. The subgroup B strain RSV B1 and its mutant cp-52 (with SH and G gene deletions) both induced similar but low levels of IFN-beta. Hence the observed overattenuation of cp-52 in human infants is probably not due to enhanced IFN induction during its replication in the host. The ability of cp-52, which does not express the SH and G proteins, to induce IFN-beta levels similar to those of its parent strain suggests that these viral proteins may not have a role in the induction of IFN-beta in the host. In addition, both subgroup A and B mutants and their respective parent strains were similarly resistant to the antiviral effects of exogenous IFN-alpha or -beta. Therefore, increased sensitivity of the mutants to IFNs does not seem to contribute to their attenuation.
评估了I型干扰素（IFN）对三种温度敏感（Ts）A亚组和一种B亚组缺失突变型呼吸道合胞病毒（RSV）株体外减毒的作用。在人肺上皮A549细胞中测试了这些疫苗病毒在其允许温度和限制温度下诱导IFN的能力以及它们对外源I型IFN抗病毒作用的敏感性。我们的结果表明，高度减毒且具有免疫原性的A亚组疫苗株Ts1C在其允许温度下产生的IFN-β水平高于其亲本RSS-2或两种相关株Ts1A和Ts1B。在限制温度下培养受RSV感染的A549细胞或事先对病毒进行紫外线灭活，消除了观察到的IFN-β诱导，这表明细胞IFN诱导严格需要病毒复制。高免疫原性的Ts1C在允许温度下增强的IFN-β诱导可能是活鼻内候选疫苗的一个有利特征。B亚组毒株RSV B1及其突变体cp-52（具有SH和G基因缺失）均诱导了相似但较低水平的IFN-β。因此，观察到的cp-52在人类婴儿中的过度减毒可能不是由于其在宿主体内复制期间IFN诱导增强所致。不表达SH和G蛋白的cp-52诱导IFN-β水平与其亲本株相似，这表明这些病毒蛋白可能在宿主体内IFN-β的诱导中不起作用。此外，A亚组和B亚组突变体及其各自的亲本株对外源IFN-α或-β的抗病毒作用同样具有抗性。因此，突变体对IFN的敏感性增加似乎并未导致其减毒。
