IFN‐α subtypes: distinct biological activities in anti‐viral therapy

Abstract

During most viral infections, the immediate host response is characterized by an induction of type I IFN. These cytokines have various biological activities, including anti‐viral, anti‐proliferative and immunomodulatory effects. After induction, they bind to their IFN‐α/β receptor, which leads to downstream signalling resulting in the expression of numerous different IFN‐stimulated genes. These genes encode anti‐viral proteins that directly inhibit viral replication as well as modulate immune function. Thus, the induction of type I IFN is a very powerful tool for the host to fight virus infections. Many viruses evade this response by various strategies like the direct suppression of IFN induction or inhibition of the IFN signalling pathway. Therefore, the therapeutic application of exogenous type I IFN or molecules that induce strong IFN responses should be of great potential for future immunotherapies against viral infections. Type I IFN is currently used as a treatment in chronic hepatitis B and C virus infection, but as yet is not widely utilized for other viral infections. One reason for this restricted clinical use is that type I IFN belongs to a multigene family that includes 13 different IFN‐α subtypes and IFN‐β, whose individual anti‐viral and immunomodulatory properties have so far not been investigated in detail to improve IFN therapy against viral infections in humans. In this review, we summarize the recent achievements in defining the distinct biological functions of type I IFN subtypes in cell culture and in animal models of viral infection as well as their clinical usage in chronic hepatitis virus infections.

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…This observation is consistent with previous studies showing that innate responses in the mucosa immediately following infection are inducing a potent antiviral state through the up-regulation of ISGs, many of which have anti-HIV-1 activity (63,64,(66)(67)(68)(69)(70)(71)(72)(73). All IFN subtypes signal through the same heterodimeric receptor (30), but differences in receptor binding and/or downstream signal transduction pathways are thought to be responsible for IFN subtype-specific biological effects (74)(75)(76)(77). IFNβ has been reported to bind the IFN receptor (IFNAR) with the highest affinity (76) and ligates the IFNAR1 chain in an IFNAR2-independent manner, resulting in the expression of a distinct set of genes (78).…”

Antiviral Activities of Different Interferon Types and Subtypes against Hepatitis E Virus Replication

“…Although the 13 known IFN-␣ subtypes display unique activity profiles (12), only the IFN-␣2a and IFN-␣2b subtypes have been licensed for the treatment of viral infections (13). To evaluate the potency of the different IFN-␣ subtypes against HEV, subgenomic HEV replicon cells were incubated with either 250 IU (Fig.…”

“…Mammalian IFNs are divided into three types, each using their unique receptor complex: type I is mainly represented by IFN-␣ and -␤, type II by IFN-␥, and type III comprising IFN- (11). IFN-␣ can be further divided into 13 subtypes which exhibit a high degree of amino acid similarity (Ͼ75%); all bind to the same receptor but still display a unique activity profile (12) and differ in their biological activities (13). IFN-␥ is the sole representative of type II IFN, while the IFN type III family is the most recently discovered group of IFNs, comprising IFN-1 to -4 (14).…”

Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

“…Type I IFN also has antiproliferative, proapoptotic, antiangiogenic, and immunoregulatory activities in addition to antiviral activity (37,38). Although no unique functions have been defined for IFN-␣ relative to those of IFN-␤ (39), distinct IFN subtypes are capable of differentially inducing biological responses despite signaling through a shared receptor (40,41). Although all type I IFN subtypes are similarly effective at inducing antiviral gene expression, IFN-␤ regulates cellular functions such as growth and apoptosis at concentrations that are orders of magnitude lower than those for any of the IFN-␣ subtypes (38).…”

“…This is due in part to the capacity of IFN-␤ to bind with higher affinity and form more stable ternary complexes with IFNAR1 and IFNAR2 (42)(43)(44). Differential immunoregulatory capacities also have been noted for IFN-␤ and -␣ and among IFN-␣ subtypes (41,45,46). In addition to ligand binding affinity, differential induction of biological responses by IFN-␤ and -␣ has been attributed to IFNAR-1 and -2 expression levels, receptor trafficking (degradation versus recycling), and the presence of cell-and tissue-specific regulatory factors (38,45,(47)(48)(49).…”