In Vitro and In Vivo Activity of Ribavirin against Andes Virus Infection

David Safronetz,Friederike Feldmann,Heinz Feldmann,Hideki Ebihara,Elaine Haddock,Daniel G Bausch

doi:10.1371/journal.pone.0023560

Abstract

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.

Highlights

Hantaviruses are a global threat to public health and are associated with two diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and the more recently recognized hantavirus pulmonary syndrome (HPS), known as hantavirus cardiopulmonary syndrome (HCPS) to highlight the importance of cardiogenic shock in severe disease
Reductions of viral RNA in the cell culture supernatant of Andes virus (ANDV) infected Vero cells treated with ribavirin were observed throughout the course of a 7 day infection, with statistically significant differences noted on days 1 (p = 0.0023) and 3 p.i. (p = 0.0073) at ribavirin concentrations of 25 mg ml21 or greater and on day 7 p.i. at concentrations of 50 mg ml21 or greater (p,0.0001, Figure 1B)
Similar reductions in viral RNA were observed in cell lysates with statistically significant results noted on days 1 (p = 0.0161) and 3 p.i. (p,0.0001) in cells treated with ribavirin at concentrations of 25 mg ml21 or greater and on day 7 p.i. at concentrations of 50 mg ml21 or greater (p,0.0001, Figure 1C)

Summary

Introduction

Hantaviruses (family Bunyaviridae, genus Hantavirus) are a global threat to public health and are associated with two diseases in humans, hemorrhagic fever with renal syndrome (HFRS) and the more recently recognized hantavirus pulmonary syndrome (HPS), known as hantavirus cardiopulmonary syndrome (HCPS) to highlight the importance of cardiogenic shock in severe disease. A two year prospective clinical trial conducted in China demonstrated that intravenous ribavirin therapy had a statistically significant positive effect, in HFRS patients, with reduced morbidity and mortality observed in the treatment group when compared to the placebo control group [13]. These findings are supported by a recent study conducted in Korea which found treatment with intravenous ribavirin resulted in decreased renal complications compared to a non-ribavirin treated cohort of confirmed HFRS cases [14]

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