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
Human parainfluenza virus type 3 is a significant cause of severe respiratory illnesses, especially in young children, older adults, and individuals with weakened immune systems. Currently, there are no antiviral medications specifically approved to treat infections caused by this virus. In this study, we found that combining ribavirin, a known antiviral drug, with either remdesivir or its parent nucleoside, GS-441524, resulted in a strong antiviral effect against human parainfluenza virus type 3 in laboratory studies using LLC-MK2 cells and in human airway epithelial cells grown in a way that mimics the air-liquid interface of the respiratory tract.
In a mouse model of human parainfluenza virus type 3 infection, using AG129 mice that lack certain immune functions, the combined treatment with ribavirin and GS-441524 significantly reduced the amount of infectious virus in the lungs. Specifically, the viral load was decreased by more than 2.5 logarithmic units to undetectable levels in 4 out of 11 mice, and by 1.6 logarithmic units in the remaining 7 mice, when compared to mice that received only a control solution. Furthermore, the lungs of all mice that received the combined treatment appeared normal or almost normal upon histological examination.
In contrast, 8 out of 11 mice that received the control solution showed signs of bronchopneumonia, a severe lung inflammation. Interestingly, treatment with ribavirin alone did not lead to a reduction in the amount of infectious virus in the lungs, while GS-441524 alone resulted in a 1.2 logarithmic unit reduction in viral load.
Moreover, several mice in the groups that received only one of the drugs exhibited severe lung pathology. These findings suggest that further investigation into the combination of ribavirin and either remdesivir or GS-441524 may be warranted for the treatment of patients with severe human parainfluenza virus type 3 infections, and potentially also against infections caused by other viruses that are susceptible to these two drugs in laboratory settings.