Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.
PLoS One. 2011;6(8):e23560. doi: 10.1371/journal.pone.0023560. Epub 2011 Aug 10.
Pathogenic hantaviruses are a closely related group of rodent-borne viruses which are responsible for two distinct diseases in humans, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS, otherwise known as hantavirus cardiopulmonary syndrome, HCPS). The antiviral effect of ribavirin against Old World hantaviruses, most notably Hantaan virus, is well documented; however, only a few studies have addressed its inhibitory effect on New World hantaviruses. In the present study, we demonstrate that ribavirin is highly active against Andes virus (ANDV), an important etiological agent of HPS, both in vitro and in vivo using a lethal hamster model of HPS. Treatment of ANDV infected Vero E6 cells with ribavirin resulted in dose-dependent reductions in viral RNA and protein as well as virus yields with a half maximal inhibitory concentration between 5 and 12.5 µg ml(-1). In hamsters, treatment with as little as 5 mg kg(-1) day(-1) was 100% effective at preventing lethal HPS disease when therapy was administered by intraperitoneal injection from day 1 through day 10 post-infection. Significant reductions were observed in ANDV RNA and antigen positive cells in lung and liver tissues. Ribavirin remained completely protective when administered by intraperitoneal injections up to three days post-infection. In addition, we show that daily oral ribavirin therapy initiated 1 day post-infection and continuing for ten days is also protective against lethal ANDV disease, even at doses of 5 mg kg(-1) day(-1). Our results suggest ribavirin treatment is beneficial for postexposure prophylaxis against HPS-causing hantaviruses and should be considered in scenarios where exposure to the virus is probable. The similarities between the results obtained in this study and those from previous clinical evaluations of ribavirin against HPS, further validate the hamster model of lethal HPS and demonstrate its usefulness in screening antiviral agents against this disease.
致病性汉坦病毒是一组密切相关的啮齿动物传播病毒，可导致人类两种不同的疾病，即肾综合征出血热和汉坦病毒肺综合征（HPS，也称为汉坦病毒心肺综合征，HCPS）。利巴韦林对旧世界汉坦病毒，尤其是汉坦病毒，具有良好的抗病毒作用已得到充分证实；然而，只有少数研究探讨了其对新世界汉坦病毒的抑制作用。在本研究中，我们证明利巴韦林对安第斯病毒（ANDV）具有高度活性，ANDV 是 HPS 的重要病原体，无论是在体外还是使用致命的 HPS 仓鼠模型。用利巴韦林处理 ANDV 感染的 Vero E6 细胞可导致病毒 RNA 和蛋白质以及病毒产量呈剂量依赖性降低，半最大抑制浓度在 5 和 12.5μg/ml 之间。在仓鼠中，当从感染后第 1 天至第 10 天通过腹腔注射给药时，每天低至 5mg/kg 的剂量可 100%有效预防致命的 HPS 疾病。在肺和肝组织中观察到 ANDV RNA 和抗原阳性细胞的显著减少。当在感染后 3 天内通过腹腔注射给予利巴韦林时，它仍然完全具有保护作用。此外，我们表明，即使在 5mg/kg 天剂量下，从感染后第 1 天开始并持续 10 天的每日口服利巴韦林治疗也可预防致命的 ANDV 疾病。我们的结果表明，利巴韦林治疗对 HPS 引起的汉坦病毒暴露后预防有益，并且在病毒暴露可能的情况下应考虑使用。本研究中获得的结果与先前对利巴韦林治疗 HPS 的临床评估结果相似，进一步验证了致命性 HPS 仓鼠模型，并证明了其在筛选针对这种疾病的抗病毒药物中的有用性。
