Lineage-dependent differences and the role of IFITM3 in the type-I interferon-induced restriction of Zika virus

Type-I interferon (IFN-I) is an important aspect of host innate antiviral response. Recent studies have shown that IFN-I can inhibit Zika virus (ZIKV) replication and that this is mediated in part by Interferon-induced transmembrane protein 3 (IFITM3). ZIKV infections in South America have led to severe congenital syndrome in a subset of infected infants. ZIKV was first identified in Africa, where there is limited evidence for the pathogenic effects associated with the American outbreak, which is fueled by infection with Asian-lineage strains, raising the possibility that the African and Asian ZIKV lineages have distinct pathogenic properties. Given the observation that IFN-I can inhibit ZIKV replication in cell culture, we asked whether ZIKV strains differed in their susceptibility to IFN-I. There was a range of susceptibilities to IFN-I inhibition across virus strains. Virus production in A549 cells was reduced from 3-42-fold for IFNα and 63-807-fold for IFNβ across a panel of nine viruses, five from the African-lineage and four from the Asian-lineage. African-lineage ZIKV strains were more resistant to IFN-I than Asian-lineage strains, but this difference was only significant for IFNα-mediated restriction (p = 0.049). Notably, over-expression of IFITM3 at similar levels induced by IFN-I did not significantly restrict either a prototype African lineage (MR 766) or Asian lineage (PRVABC59) isolate. Moreover, knocking out IFITM3 expression did not result in a significant increase in viral replication or a diminishment of the inhibition by IFN-I. Overall, our findings show that while diverse ZIKV strains are susceptible to the antiviral effects of IFN-I, African-lineage strains are more resistant to IFNα. In addition, the majority of the IFN-I-induced inhibition of ZIKV strains cannot be explained by IFITM3, suggesting that other unknown ISGs may be the driving force of the type I IFN response against ZIKV.Author summaryThe innate immune system, and specifically the type-I interferon response, is a critical component of the host response against viral infections. The recent unprecedented spread and severe pathogenic features of Zika virus in the Americas have led to significant interest in characterizing features of Zika virus strains that have fueled the American outbreak. Zika virus was first identified in Africa, where there is limited evidence for the pathogenic effects associated with the American outbreak. Here, we demonstrate that African-lineage Zika virus strains are significantly more resistant to the effects of type-I interferon, and that type-I interferon-mediated restriction of Zika virus strains is not explained by the host factor Interferon-induced transmembrane protein 3. This improved understanding of Zika virus-host interactions may explain certain pathogenic features of Asian-lineage Zika virus strains that have fueled the American Zika virus epidemic, and supports the search for as-yet-unidentified actors in the interferon response against Zika virus.