**2. Interferons**

Interferon family represents a widely expressed group of cytokines. It includes three main classes, designated as type I IFNs, type II IFN and type III IFNs. The two main type I IFNs includes IFN-α (further classified into 13 different subtypes such as IFN-α1, -α2, -α4, -α5, -α6, -α7, -α8, -α10, -α13, -α14, -α16, -α17 and -α21), and IFN-β. The term *interferon* derives from the ability of these cytokines to interfere with viral replication. Type I IFNs present a potent antiviral effect by inhibiting viral replication, increasing the lysis potential of natural killer (NK) cells and the expression of MHC class I molecules on virus-infected cells, and stimulating the development of Th1 cells. During an infectious process, this type of interferon becomes abundant and is easily detectable in the blood. On the other hand, type II IFN has only one representative, IFN-γ. This cytokine plays a major role is macrophage activation both in innate and adaptive immune responses. Type III IFNs, also denoted IL-28/29, present similar biological effects to type I IFN, playing an important role in host defense against viral infections [5–8].

### **2.1. History**

Interferon was the first described member of the class of protein molecules now known as cytokines. Nowadays, interferons are well known to participate in innate immune system, mediating responses against viral infections. This role of the IFNs was first described in the 1930s, when a research conducted by Hoskins demonstrated that rabbits previously infected by the herpes simplex virus were protected against subsequent infections by the same type of virus. In 1937, a few years after Hoskins' experiment, Findlay and MacCallum showed that the virus-infected animals were also resistant to infections caused by antigenically different viruses, corroborating and complementing the existing evidence regarding IFNs functions at that time. Their findings, however, were only confirmed in 1957, when Isaacs and Lindenmann, through cell cultures research, demonstrated that cells infected by a virus had the ability to produce a protein that could make other cells resistant to other viruses. Glasgow, in 1966, theorized that the interferon production was not limited to primary infection by viruses, and that this cytokine might play a role following re-infection. Therefore, the concept of "immune induction" of interferon became well established by the end of the 1960s. The early 1970s were marked by two milestone studies, which confirmed the existence of two different categories of interferons, which differed physicochemically and biologically: the immune-induced interferon (currently known as type II IFN) and the classical virus-induced interferon (currently known as type I IFN). In 1980, the terms IFN-α and IFN-β arose to designate the "classical interferons", which had been obtained in pure forms exhibiting homogeneity. Albeit the "immune-induced interferon" had not been obtained in pure form at that time, it was recognized that this molecule was different from IFN-α and IFN-β, being, therefore, designated as IFN-γ. Despite the markedly difference of this cytokine when compared to IFN-α and IFN-β, IFN-γ was originally classified in the IFN family due to its ability to 'interfere' with viral infections, which characterizes the original definition of IFNs. In the last decade, a third type of IFN (type III IFN) has been described, the IFN-λ. This type is also referred as interleukins IL-28A and B (IFN-λ2 and IFN-λ3, respectively), and IL-29 (IFN-λ1) [8–11].
