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Chapter 18 : Targeting the Interferon Response for Antiviral Therapy

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Abstract:

This chapter provides a general introduction and overview of the interferon (IFN) pathway. Separate sections of this chapter address the different types of IFN, activation of IFN-α/β expression, IFN-mediated signal transduction, antiviral mechanisms, and viral resistance to the IFN-α/β response. The IFNs are classified into three types (I, II, and III) based on receptor usage, sequence homology, and chromosome location of their genes. The chapter primarily focuses on the type I IFNs, as these cytokines are most closely associated with antiviral activity and therapeutic use. Like RNA, cytosolic DNA also induces the production of IFN-β. Therefore, in addition to RNA viruses, a mechanism also exists to detect the genomes from DNA viruses in the cytoplasm of infected cells. The Toll-like receptors (TLRs) are critical for recognizing different molecular patterns that are unique to viral or bacterial pathogens. As with the cytoplasmic sensors, specificity for pathogen-derived nucleic acids by the TLRs is at least in part provided at the level of nucleic acid modifications. IFN-α/β is important for certain aspects of the adaptive immune response and serves as one example of a bridge between innate and adaptive immunity. In addition to antiviral and immunomodulatory functions, IFN-α/β can also negatively influence cellular proliferation. Future research into improved IFN-based antiviral therapies might focus on improving the antiviral properties of these cytokines while decreasing the unwanted side effects. This goal might be accomplished in a number of distinct ways.

Citation: Robek M. 2009. Targeting the Interferon Response for Antiviral Therapy, p 317-332. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch18

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Figure 1.

IFN-β induction by dsRNA. Binding of dsRNA to TLR3 in endosomes leads to signaling through the TRIF adapter protein to activate the kinases TBK-1 and IKK-∊. Similarly, RNA binding to RIG-I or MDA5 in the cytoplasm leads to interaction with the mitochondrial protein IPS-1, followed by activation of the same kinases. These kinases in turn phosphorylate IRF-3, which then dimerizes, translocates to the nucleus, and activates IFN-β mRNA expression. IFN-β protein synthesized in the cytoplasm is then released from the cell. This process can be interrupted at various steps by viral proteins, including vaccinia virus E3L, which sequesters dsRNA; HCV NS3/4A, which cleaves IPS-1 and TRIF; KSHV vIRF, which inhibits IRF-3 function; and VSV matrix (M), which blocks mRNA export.

Citation: Robek M. 2009. Targeting the Interferon Response for Antiviral Therapy, p 317-332. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch18
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Image of Figure 2.
Figure 2.

IFN-α/β and IFN-γ receptor signaling. Binding of IFN-α/β or IFN-γ to their respective receptor activates Jak and Tyk tyrosine kinases to phosphorylate STAT proteins. After phosphorylation, the STATs dimerize and translocate to the nucleus, where they initiate transcription from specific promoter elements. The IFN-α/β receptor induces the activation of STAT-1/STAT-2 heterodimers, which when bound to IRF-9 activate IFN-stimulated gene expression from ISRE sequences. Likewise, the IFN-γ receptor induces the formation of STAT-1 homodimers, which bind and activate GAS elements. As with IFN-α/β induction, this process can be inhibited by viral proteins at multiple steps. Some examples include vaccinia virus B8R and B18R, which bind and neutralize extracellular IFN-α and IFN-γ; KSHV K3 and K5, which downregulate IFN-γ receptor from the cell surface; paramyxovirus V proteins, which inhibit STAT activation; and rabies P protein, which sequesters STAT proteins in the cytoplasm, preventing their nuclear import.

Citation: Robek M. 2009. Targeting the Interferon Response for Antiviral Therapy, p 317-332. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch18
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