Abstract
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.
Highlights
Type I IFNs belong to a multigene family consisting of numerous IFNa subtypes but only one IFNb, IFNε, IFNk, and IFNz/limitin [1]
That during acute lymphocytic choriomeningitis virus (LCMV) infection type I IFNs contribute to the control of viral infection, whereas during chronic LCMV infection, IFNb, in contrast to IFNa, has a rather detrimental role and contributed to immune dysfunction during persistent LCMV infection
Type I IFNs have a short half-life in vivo, so it was not surprising that 24 hours after the last IFN injection, levels of IFNa were similar between treated mice and Friend retrovirus (FV)-infected controls (Figure 1D)
Summary
Type I IFNs belong to a multigene family consisting of numerous IFNa subtypes but only one IFNb, IFNε, IFNk, and IFNz/limitin [1]. Combination therapy of antiretroviral drugs together with IFNa14 further reduced the viral loads in chronically HIV-infected humanized mice [12], suggesting that IFN therapy with the right subtype (increased antiviral and immunomodulatory activity, reduced side effects) might still be an option to treat HIV infection. Several studies showed that a type I IFN signature in chronically HIV-infected humanized mice was associated with T cell dysfunction and a lack of immune control of the virus [19–21]. They suggested that IFN therapy might be detrimental during chronic HIV infection, but they did not distinguish between IFNb and IFNa responses. IFNa might still be an option for the treatment of chronic infections, including HIV
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