Autoantibodies neutralizing type I interferons (IFN-Is
IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by neutralizing IFN-I autoantibody-containing plasmas from aged individuals with HIV-1 and from individuals with severe COVID-19. These faces overlap with IFN-I regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, and neutralizing plasmas efficiently block the interaction of IFN-I with both receptor subunits in vitro. In contrast, non-neutralizing autoantibody-containing plasmas limit the interaction of IFN-I with only one receptor subunit and display relatively low IFN-I-binding avidities, thus likely hindering neutralizing function. Iterative engineering of signaling-inert mutant IFN-Is (simIFN-Is) retaining dominant autoantibody targets created potent decoys that prevent IFN-I neutralization by autoantibody-containing plasmas and that restore IFN-I-mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting IFN-I autoantibodies from plasmas, leaving antiviral antibodies unaffected. Our study reveals mechanisms of action for IFN-I autoantibodies and demonstrates a proof-of-concept strategy to alleviate pathogenic effects.