Inhibition of type I interferon responses by adenovirus serotype-dependent Gas6 binding

Abstract

The clinical use of many adenovirus vaccine vectors (AdVs) is limited by the presence of pre-existing antibodies in human populations, which prevent common AdVs from transducing cells and expressing immunogenic gene products. Rare serotype AdVs, such as HAdV-28D can bypass pre-existing immunity. However, rare AdVs stimulate high-levels of type I interferon (IFN), which suppresses antigenic gene expression and therefore limits immunogenicity. Recent studies identified Gas6 as a factor that connects enveloped viruses to host-cell receptor tyrosine kinases, in turn generating signaling cascades that antagonize type I IFN responses. We discovered that Gas6 bound to the fiber proteins of common AdV serotypes, such as HAdV-5C, with a higher affinity than rare HAd-28D fibers. AdV-associated Gas6 suppressed IFN production by common AdVs and enhanced long-term expression of AdV encoded genes. We hypothesize that rare AdV serotypes might be engineered to include Gas6 binding motifs, thereby generating novel vectors that are more effective.

Keywords: Adenovirus; Gas6; Gene therapy; Innate immunity; TAM receptors; Type I interferons; Vaccine vectors.