Zika Virus Infection: Induction, Restriction and Evasion of Host Interferon Responses

Abstract

Zika virus (ZIKV) is an arthropod-borne flavivirus that has become a significant global health concern due to its rapid geographic expansion and association with novel neurological pathogenesis [1]. The recent emergence of ZIKV is multifactorial and likely includes the expanded geographical range of Aedes sp. mosquitoes, the immunological naivety of human populations outside of historically endemic regions and global travel of infected individuals [2]. In addition to these epidemiological consequences of globalization, ZIKV has evolved novel mechanisms to induce disease pathogenesis and evade host immune responses [1,2]. Understanding how recently acquired viral polymorphisms influence viral pathogenesis and the host immune response during infection is crucial to further our understanding of ZIKV infection and pathogenesis.ZIKV is a single-stranded, positive-sense RNA virus that encodes a single polyprotein that is catalytically processed by host and viral proteases into three structural proteins (C, prM and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). The structural proteins form the virion particle are the primary targets for the host humoral immune response [1,2]. The multifunctional nonstructural proteins have been implicated in polyprotein processing, viral RNA replication, virion assembly, as well as evasion of the innate immune response [1]. Herein, we review recent findings regarding how the interferon (IFN) response restricts ZIKV infection and the ways in which ZIKV is able to overcome IFN signaling to circumvent innate immunity. Type I IFN stimulated genes restrict ZIKV infectionType I IFNs (IFNα/β) are transcriptionally regulated and induced following recognition of pathogen components during infection by various host pattern recognition receptors. Activation of pattern recognition receptors leads to synthesis of type I IFNs that trigger antiviral responses by binding to a common type I IFN receptor. Receptor binding stimulates the JAK kinases, which phosphorylate STAT1 and STAT2, leading to the assembly of the ISGF3 complex, composed of STAT1-STAT2 dimers and IRF9, which translocates to the nucleus and binds to IFN-stimulated response elements in the promoters of interferon stimulated genes (ISGs) to regulate their expression [3,4]. This signaling cascade leads to the transcription of more than 300 ISGs, creating a cellular environment resistant to viral replication. It is well established that type I IFN induction is able to restrict ZIKV infection in cell culture [5][6][7][8] and in mouse models [6,9].Recent investigations have demonstrated that several ISGs are able to restrict ZIKV infection [10]. Specifically, the IFN-induced transmembrane proteins, IFITM2 and IFITM3, have been shown to restrict infection at early stages of the viral life cycle and provide protection against ZIKV-induced cytopathic effects in HeLa cells [10]. Additionally, viperin, another antiviral ISG, is able to restrict replication in human hepatoma cells; and viperin knockout mouse embryo...