While ISG15 expression is upregulated in the context of in vivo infection with several flaviviruses [17,41], the antiviral role of ISG15 in WNV infection in vivo has been called into doubt: ISG15-/- mice did not appear to have increased susceptibility to WNV infection despite apparent in vitro antiviral activity of ISG15 towards WNV [40,42]. This evidence concerns the gene ISG15 and infection.