The combination of GS-441524 (remdesivir) and ribavirin results in a potent antiviral effect against human parainfluenza virus 3 infection in human airway epithelial cell cultures and in a mouse infection model

Abstract

Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory diseases, particularly in young children, the elderly and immunocompromised. There are no approved antiviral drugs against this virus. We report that the combination of ribavirin with either remdesivir or its parent nucleoside GS-441524 results in a pronounced antiviral effect against HPIV-3 in LLC-MK2 cells and in human airway epithelial cells grown at the air-liquid interface. In AG129 mice intranasally inoculated with HPIV-3, the combined treatment of ribavirin and GS-441524 decreases infectious viral lung titers by >2.5 log10 to undetectable levels in 4 out of 11 mice and by 1.6 log10 in the remaining 7 mice as compared with vehicle. The lungs of all mice that received the combined treatment appear histologically normal or virtually normal, whereas 8 of 11 vehicle-treated mice present with bronchopneumonia. By contrast, ribavirin alone does not result in a reduction of infectious viral lung titers; GS-441524 alone reduces infectious viral lung titers by 1.2 log10. Moreover, several mice in the single-treatment groups exhibit severe lung pathology. These findings may warrant exploring this combination in patients with severe HPIV-3 infections and possibly also against infections with other viruses that are in vitro susceptible to these two drugs.