Abstract
Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route.
Highlights
Hantaviruses are enzootic viruses of rodents which cause two severe vascular-leak diseases in humans [1], hemorrhagic fever virus with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS)
Ribavirin has been employed in treatment of several human diseases caused by different hemorrhagic fever viruses including the Old World hantavirus, Hantaan virus (HTNV) [41,46,47], and we provide an extensive evaluation of its efficacy in the i.n. challenge model of lethal Andes virus (ANDV) infection of adult hamsters
After removing virally infected media and washing the cells in PBS, the media was replaced with complete essential medium with Earle’s salts (EMEM) containing ribavirin (ICN Pharmaceuticals, Costa Mesa, CA, USA) at concentrations ranging from 0–70 μg/mL and the cells were incubated at 37 °C and 5% CO2
Summary
Hantaviruses are enzootic viruses of rodents which cause two severe vascular-leak diseases in humans [1], hemorrhagic fever virus with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). In the lethal, suckling mouse model of HFRS with HTNV, ribavirin can prevent mortality when treatment is begun as late as 6 days post-infection [31]. Antiviral compound derivatives based upon the structure of ribavirin have shown success at limiting hantaviral replication, for both HFRS and HPS associated hantaviruses, in vitro and in vivo with lower. A recent investigation shows that treatment needs to begin before the oliguric phase to prevent mortality [41] In these clinical studies using intravenous ribavirin treatment of HFRS, human cases caused by HTNV show improvement with a decrease in occurrence of oliguria and severity of renal insufficiency [41]. These studies show the definite potential ribavirin has as an effective antiviral treatment for HPS
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