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Type I interferons (IFNs) are critical for the innate defense against viruses. However, long-term or chronic production of Type I IFNs may promote autoimmune diseases such as systemic lupus erythematosus (SLE; lupus). Data also suggest that Type I IFN may contribute to the persistence of some viral infections. There is a need for robust Type I IFN antagonists for understanding the in vivo role(s) of Type I IFNs, and to potentially block IFN when it causes or exacerbates a pathologic condition. We previously described an interferon analogue, “IFN-Ant1” (IFN-α2[Arg120Glu]-8CT) that was derived from human IFN-α2. IFN-Ant1 lacks most biological activity and acts in vitro as a partial competitive antagonist. We now report that IFN-Ant1 functions in vivo in primates. The efficacy of this antagonist was tested in rhesus macaques (N=6) challenged with simian immunodeficiency virus (SIVmac251), and treated during the acute infection stage (4weeks) with daily injections of IFN-Ant1 or placebo. Macaques were analyzed for IFN-related and immunological markers during this acute phase (4weeks) and then for an additional 6months. Treatment of the macaques with the antagonist during the acute phase of SIV infection was well tolerated and led to significant changes in several immune and virologic parameters. Among these: (1) macaques treated with IFN-Ant1 had significantly higher serum viral loads than placebo-treated; and (2) treated animals rapidly progressed to AIDS. Various molecular and immune parameters were monitored during the acute and chronic phases of the infection. These data contribute to our understanding of the role of endogenous Type I IFN during SIV infection of macaques, and provide evidence for efficacy of the antagonist in primates.