Inhibition of Zika Virus by hybrid interferons

Zika Virus (ZIKV) is a re-emerging mosquito-borne flavivirus. In most cases ZIKV infection is mild and resolve on their own. However, ZIKV is also linked to developmental abnormalities in foetuses including microcephaly and other serious neurological diseases like Guillain-Barre syndrome in adults. Despite being declared an international health emergency, we have no specific treatment or vaccine available for ZIKV infection.
Interferons (IFNs) are our bodies first line defence against viruses. Depending on their receptor usage IFNs are divided into three types, type 1, 2 and 3 IFNs. They control viral infection by inducing the expression of antiviral proteins that are encoded by interferon-stimulated genes (ISGs). The initial host response against virus infection is the induction of type 1 IFNs. There are 12 human IFN alpha (a type 1 IFN) subtypes but only IFNa 2a and 2b subtypes are used clinically. They have been approved by the FDA for the treatment of certain infections and cancers including chronic Hepatitis C, AIDS-related Kaposi sarcoma, hairy cell leukaemia, and hepatitis B in adults. However, studies have shown that IFNa 2 subtypes have weaker antiviral activity as compared to other more potent IFNa subtypes. For instance, IFNa 14 has been shown to be highly active against viruses including HIV and influenza A virus. Working with our industrial partner ILC Therapeutics, we have access to novel hybrid interferons alongside in-house synthetic and naturally occurring IFNa variants that are based on the IFNa 14 backbone.
This study aims to test if the IFNa 14 and its derivatives have antiviral activity against ZIKV infection. To do this, we aim to test different IFNa subtypes and their synthetic derivatives for their inhibition of different lineage ZIKV utilising plaque assays, reporter assays and qPCRs. We will also aim to identify the different interferon stimulated genes (ISGs) that are differentially expressed in cells stimulated with different IFNa subtypes using RNA-Seq analysis and to validate the identified ISGs with qPCR and pulse SILAC proteomic analyses. This study will also generate ISG overexpression cell lines and knock-out cells lines to test for their sensitivity and resistance to ZIKV; and to determine the role of the ZIKV protein NS5 in counteracting the antiviral activity of the different IFNa subtypes.
This will enable us to understand how hybrid interferons might control ZIKV infection and reveal the differences in therapeutic responsiveness according to viral genotype.