Human parainfluenza viruses (HPIVs) are major causes of lower respiratory tract disease, including croup and pneumonia. Viral entry is initiated when the viral receptor binding protein engages its host receptor and activates the viral fusion (F) protein. The F protein then undergoes an essential refolding process, inserting into the host membrane and collapsing into a stable six-helix bundle (6HB) structure to drive membrane fusion. This step is a promising target for antiviral peptides, which can block infection by preventing the formation of the 6HB structure. Here, we examined an HPIV variant that emerged under selection pressure from such a prototype antiviral peptide. A single mutation in F destabilized the 6HB and disrupted refolding, enabling viral spread in the presence of the antiviral peptide. However, this adaptation within a highly conserved region imposed a substantial fitness cost in the airway, underscoring the critical constraints on fusion protein function during infection in vivo.
Crosby et al. (Tue,) studied this question.