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. 2013 Nov 8;5(11):2704-20.
doi: 10.3390/v5112704.

Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome--after intranasal exposure to Andes virus

Monica Ogg  1 , Colleen B Jonsson, Jeremy V Camp, Jay W Hooper
Affiliations

Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome--after intranasal exposure to Andes virus

Monica Ogg et al. Viruses. .

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.

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Figures

Figure 1
Figure 1
Visual representation of antiviral activity of ribavirin in a comet spread assay with Andes virus (ANDV). Representative culture flasks stained for the presence of the ANDV glycoprotein are shown different days post-infection with ANDV in the presence or absence of ribavirin. ANDV staining on Day 10 at 20 and 40 μg/mL ribavirin shows an inhibition of staining or spread at 40 μg/mL ribavirin but not 20 μg/mL ribavirin. With ANDV alone, an increase in the level of stain is observed over Days 5–10.
Figure 2
Figure 2
Antiviral activity of ribavirin in a titer reduction assay with ANDV. Vero E6 cells were infected with ANDV and after specific days post-infection viral supernatant was analyzed for viral titer. The viral titers at various concentrations (0–70 μg) of ribavirin are presented.
Figure 3
Figure 3
Survival curve of hamsters with mock or ribavirin-treatment following infection with ANDV. (A) To test drug toxicity, hamsters were given either 50, 100, or 200 mg/kg/day of ribavirin, or mock treated (no ribavirin), for 21 days and then observed thru 35 days post-infection; (B) Hamsters were challenged with 4,000 pfu by the i.n. route and, starting on day 0, given either 50, 100, or 200 mg/kg/day of ribavirin, or mock treated, for 21 days. Animals were observed for signs of disease for 35 days after challenge. Treatment with ribavirin protected animals after infection with ANDV at 100 mg/kg and 50 mg/kg doses (p = 0.02 and 0.03, respectively). There was no difference between animals given 200 mg/kg after infection and animals infected without treatment, which confirms the above findings that ribavirin is lethal at a dose of 200 mg/kg; (C) Survival curve of hamsters mock or treated with 50 mg/kg/day ribavirin starting at days 6, 8, 10, 12, or 14 following infection with ANDV. All treatment groups had significantly higher survival compared to untreated (p < 0.05); (D) Animals receiving treatment began at either at day 6 or 10 post-infection survived infection with ANDV for 11, 15 or 21 days. All treatment groups had significantlyhigher survival compared to untreated (p < 0.01) Survival analyses were performed by computing pair-wise comparisons to controls using the nonparametric Mantel-Cox test and the resulting p-values were adjusted using the Holm-Bonferroni method for multiple comparisons.
Figure 4
Figure 4
Viremia in ANDV-exposed hamsters treated with ribavirin. Sera collected from ANDV-exposed hamsters from the experiments shown in Figure 3 were evaluated for the presence of infectious ANDV by plaque assay. (A) ANDV titers in hamster sera collected 2 or 3 weeks after i.n. challenge with ANDV from the 50 mg/kg/day and no treatment groups are shown. Note that the 100 mg/kg/day sera were all negative for ANDV on all time points (data not shown); (B) ANDV titers in hamster sera collected 1 or 2 weeks after i.n. challenge with ANDV. Ribavirin treatment was started on days 6, 8, 10, 12, or 14 days after challenge; (C) ANDV titers in hamster sera collected 1 or 2 weeks after i.n. challenge with ANDV. Ribavirin treatment started on day 6 or 10 and continued for 11, 15, or 21 days. Red symbols represent hamsters that ultimately developed lethal infections. Green symbols indicate animals that succumbed after anesthesia or for other causes other than HPS. Lines indicate mean ANDV titers for each group.
Figure 5
Figure 5
ELISA titers on day 35 post-ANDV infection of hamster. Titer (y-axis) is shown on Day 35 in sera collected from measurement by ELISA with antibody to the nucleocapsid protein. Various treatment and control (no treatment) groups (X-axis) are shown.
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