Mechanisms underlying the inhibition of interferon signaling by viruses

Abstract

A hallmark of the antiviral response is the induction of interferons. First discovered in 1957 by Issac and Lindeman, interferons are noted for their ability to interfere with viral replication. Interferons act via autocrine and paracrine pathways to induce an antiviral state in infected cells and in neighboring cells containing interferon receptors. Interferons are the frontline defenders against viral infection and their primary function is to locally restrict viral propagation. Viruses have evolved mechanisms to escape the host interferon response, thus gaining a replicative advantage in host cells. This review will discuss recent findings on the mechanisms viruses use to evade the host interferon response. This knowledge is important because the treatment of viral infections is a challenge of global proportions and a better understanding of the mechanisms viruses use to persist in the host may uncover valuable insights applicable to the discovery of novel drug targets.

Keywords: antiviral drug target; host–virus interaction; immune evasion; interferon; interferon signaling.

Figure 1. A summary of signaling pathways leading to the induction of interferons. Viral entry is followed by the release of the viral genome into host cells, triggering the activation of TLRs, or cytoplasmic viral sensors (RIG1 and MDA5), or the activation of the NFκB, AP-1, IRF-3, and IRF-7 signaling pathways. Collectively, these pathways lead to the induction of interferons α and β, which are encoded by the IFNA and IFNB genes respectively.

Figure 2. A summary of viral mechanisms that inhibit the upstream mediators of interferon induction. NS1 and Z proteins target RIG-1, V proteins target MDA-5, and RSV targets TLRs 7 and 8.

Figure 3. A summary of viral mechanisms that target the IRF-3, NFκB, and AP-1 signaling pathways. E6, NS1, and Npro target IRF-3; NS1, 3C, and L(pro) target NFκB; NS1 and NS5A target AP-1.

Figure 4. A summary of viral mechanisms that target the JAK-STAT signaling pathway. NS5 and V proteins prevent the activation of TYK2 and JAK1 respectively; V proteins are also involved in STAT sequestration. NS5 and SV5 degrade STAT proteins; C proteins prevent the formation of activated STAT dimers and HCV core proteins induce SOCS expression. ISRE, interferon stimulated response element; GAS, gamma interferon activation site.