The yin and yang of viruses and interferons

Abstract

Interferons (IFNs)-α/β are critical effectors of the innate immune response to virus infections. Through activation of the IFN-α/β receptor (IFNAR), they induce expression of IFN-stimulated genes (ISGs) that encode antiviral proteins capable of suppressing viral replication and promoting viral clearance. Many highly pathogenic viruses have evolved mechanisms to evade an IFN response and the balance between the robustness of the host immune response and viral antagonistic mechanisms determines whether or not the virus is cleared. Here, we discuss IFNs as broad-spectrum antivirals for treatment of acute virus infections. In particular, they are useful for treatment of re-emerging virus infections, where direct-acting antivirals (DAAs) have limited utility due to DAA-resistant mutations, and for newly emerging virus strains in which the time to vaccine availability precludes vaccination at the onset of an outbreak.

Figure 1

IFNs-α/β induce an antiviral state by regulating gene expression and protein translation. IFNs-α/β bind with high affinity to the IFNAR complex, composed of an α-chain, IFNAR1, which is structurally modified by cell membrane glycosphingolipids, galabiosylceramide (Gb2) and globotriaosylceramide (Gb3) to promote efficient IFN binding , , and a β-chain, IFNAR2. IFN binding to IFNAR induces phosphorylation of the receptor-bound tyrosine kinases, tyrosine kinase 2 (TYK2) and JAK1, leading to the subsequent regulation of: (a) protein synthesis via the activation of PI3K and mammalian target of rapamycin (mTOR); (b) histone modification, via the activation of p38 MAPK; and (c) gene expression via the phosphorylation of STAT proteins and MAPK activation. TYK2- and JAK1-mediated activation of insulin receptor substrate (IRS) 1 and IRS2 is required for recruitment and activation of PI3K. PI3K phosphorylates AKT, which inactivates inhibitors of mTOR, tuberous sclerosis protein (TSC) 1 and TSC2 . mTOR activates the serine/threonine kinase p70S6K, and inactivates eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), to upregulate cap-dependent mRNA translation and protein synthesis. p38 is activated downstream of MAPK kinases 3 and 6 (MKK3/6) and regulates histone modification and gene expression through mitogen- and stress-activated protein kinase (Msk) 1 and Msk2. In addition, IFN signaling invokes promyelocytic leukemia zinc finger (PLZF) protein-mediated histone modification to regulate ISG expression . Phosphorylation of STAT proteins results in their dimerization and IFN-stimulated gene factor (ISGF) formation. STAT complexes translocate to the nucleus and bind to specific gene elements in the promoters of ISGs, IFN-γ activated sequence (GAS) and IFN-sensitive response element (ISRE), to induce expression of antiviral genes.

Figure 2

IFNs-α/β invoke the activation of immune cells. IFN-α/β signaling modulates the innate and adaptive immune response to virus infection. (a) IFNAR⁺ cells: IFN-α/β signaling results in the expression of key antiviral factors: PKR, 2′,5′-OAS, Mx1, Mx2, ISG56/IFN-induced protein with tetratricopeptide repeats (IFIT) 1, ISG54/IFIT2 and ISG15/IFN-activated gene 15 (IFI15) . Furthermore, IFNs-α/β upregulate the expression of IFN-inducible trans-membrane protein (IFITM), an inhibitor of influenza A viruses, SARS-CoV, dengue virus and West Nile virus infections , , tripartite motif-containing protein 5α (TRIM5α) and TRIM22, which are antiviral factors that limit HIV-1 infection , and transcription factor jun-D (JUND) and claudin 4 (CLDN4) . IFN treatment primes cells for apoptosis by modulating the expression of proteasome subunits, major histocompatibility complex (MHC) class I, and FAS receptor (CD95) , , , . IFNs-α/β also contribute to the activation and differentiation of cells involved in the (b) innate and (c) adaptive immune responses to virus infection. IFN-α/β induces production of interleukin (IL)-6, IL-12, and IL-15 by DCs, and IL-10 by macrophages to modulate B and T cell differentiation (Th1 polarization) and activation . IFN-β signaling in pDCs leads to altered CD69 and sphingosine-1-phosphate 4 (S1P4) receptor expression, thereby affecting pDC retention in lymph nodes . IFNs-α/β increase MHC class II, CD40 and CD86 expression on antigen presenting cells. IFN-α/β treatment induces macrophage and neutrophil phagocytosis , . Moreover, IFNs-α/β promote neutrophil survival by activating cellular inhibitor of apoptosis 2 (cIAP2) . Natural killer (NK) cells respond to IFNs-α/β with increased FAS ligand (FASL) and perforin expression, and IFN-γ production , . In response to IFNs-α/β, B cells upregulate l-selectin and IgG production , .