West Nile virus-induced cytoplasmic membrane structures provide partial protection against the interferon-induced antiviral MxA protein

The human MxA protein is a type I and III interferon (IFN)-induced protein with proven antiviral activity against RNA viruses. In this study, we investigated the effect of MxA expression on the replication of West Nile Virus strain Kunjin (WNVKUN). Pretreatment of A549 cells with IFN-alpha lead to increased expression of MxA, which contributed to inhibition of WNVKUN replication and secretion. However, in Vero cells stably expressing the MxA protein, WNVKUN replication, maturation and secretion was not inhibited. Biochemical and subcellular localization studies of WNVKUN proteins and MxA suggest that the MxA activity was not compromised by a flavivirus-encoded antagonist. Instead, we show that characteristic membranous structures induced during WNVKUN replication provide partial protection from MxA, possibly by 'hiding' WNVKUN replication components. This distinct compartmentalization of viral replication and components of the cellular antiviral response may be an evolutionary mechanism by which flaviviruses can hide from host surveillance.