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Type I interferons (IFNs) present the first line of defense against viral infections, providing antiviral, immunomodulatory and antiproliferative effects. The type I IFN family contains 12 IFNα subtypes and IFNβ, and although they share the same receptor, they are classified as non-redundant, capable to induce a variety of different IFN-stimulated genes. However, the biological impact of individual subtypes remains controversial. Recent data propose a subtype-specificity of type I IFNs revealing unique effector functions for different viruses and thus expanding the implications for IFNα-based antiviral immunotherapies. Despite extensive research, drug-resistant infections with herpes simplex virus type 1 (HSV-1), which is the common agent of recurrent orogenital lesions, are still lacking a protective or curing therapeutic. However, due to the risk of generalized infections in immunocompromised hosts as well as the increasing incidence of resistance to conventional antiherpetic agents, HSV infections raise major health concerns. Based on their pleiotropic effector functions, the application of type I IFNs represents a promising approach to inhibit HSV-1 replication, to improve host immunity and to further elucidate their qualitative differences. Here, selective IFNα subtypes and IFNβ were evaluated for their therapeutic potential in genital HSV-1 infections. Respective in vivo studies in mice revealed subtype-specific differences in the reduction of local viral loads. IFNβ had the strongest antiviral efficacy against genital HSV-1 infection in mice, whereas IFNα1, IFNα4, and IFNα11 had no impact on viral loads. Based on flow cytometric analyses of underlying immune responses at local and peripheral sites, these differences could be further assigned to specific modulations of the antiviral immunity early during HSV-1 infection. IFNβ led to enhanced systemic cytokine secretion and elevated cytotoxic responses, which negatively correlated with viral loads in the vaginal tract. These data provide further insights into the diversity of type I IFN effector functions and their impact on the immunological control of HSV-1 infections.

The expression of type I interferons (IFNs) is one of the immediate host responses during most viral infections. The type I IFN family consists of numerous highly conserved IFNα subtypes, IFNβ, and some others. Although these IFNα subtypes were initially believed to act interchangeably, their discrete biological properties are nowadays widely accepted. Subtype-specific antiviral, immunomodulatory, and anti-proliferative activities were reported explained by differences in receptor affinity, downstream signaling events, and individual IFN-stimulated gene expression patterns. Type I IFNs and increased IFN signatures potentially linked to hyperimmune activation of T cells are critically discussed for chronic HIV (human immunodeficiency virus) infection. Here, we aimed to analyze the broad immunological effects of specific type I IFN subtypes (IFNα2, IFNα14, and IFNβ) on T and NK cell subsets during HIV-1 infection in vitro and ex vivo. Stimulation with IFNα14 and IFNβ significantly increased frequencies of degranulating (CD107a+) gut-derived CD4+ T cells and blood-derived T and NK cells. However, frequencies of IFNγ-expressing T cells were strongly reduced after stimulation with IFNα14 and IFNβ. Phosphorylation of downstream molecules was not only IFN subtype-specific; also, significant differences in STAT5 phosphorylation were observed in both healthy peripheral blood mononuclear cells (PBMCs) and PBMCs of HIV-infected individuals, but this effect was less pronounced in healthy gut-derived lamina propria mononuclear cells (LPMCs), assuming cell and tissue specific discrepancies. In conclusion, we observed distinct type I IFN subtype-specific potencies in stimulating T and NK cell responses during HIV-1-infection.

Type I Interferons (IFNs), including numerous IFNα subtypes and IFNβ, are key molecules during innate and adaptive immune responses against viral infections. These cytokines exert various non-redundant biological activities, although binding to the same receptor. Persistent viral infections are often characterized by increased IFN signatures implicating a potential role of type I IFNs in disease pathogenesis. Using the well-established Friend retrovirus (FV) mouse model, we compared the therapeutic efficacy of IFNα11 and IFNβ in acute and chronic retroviral infection. We observed a strong antiviral activity of both IFNs during acute FV infection, whereas only IFNα11 and not IFNβ could also control persistent FV infection. The therapeutic treatment with IFNα11 induced the expression of antiviral IFN-stimulated genes (ISG) and improved cytotoxic T cell responses. Finally, dysfunctional CD8+ T cells solely regained cytotoxicity after IFNα11 treatment. Our data provide evidence for opposing activities of type I IFNs during chronic retroviral infections. IFNβ was shown to be involved in immune dysfunction in chronic infections, whereas IFNα11 had a strong antiviral potential and reactivated exhausted T cells during persistent retroviral infection. In contrast, during acute infection, both type I IFNs were able to efficiently suppress FV replication.