LAUSR

Significance GBPs and IFITMs are potent innate immune restriction factors that can inhibit viral infectivity. Specifically, GBPs perturb furin-mediated processing of viral envelope proteins, targeting viruses that rely on proteolytic processing for optimal infectivity. Here, we report that GBP2 and GBP5 inhibit the cleavage of SARS-CoV-2 spike and reduce viral infection. Notably, while the infectivity of early-lineage SARS-CoV-2 isolates is restricted by GBP2/5, VOCs Alpha and Delta have evolved to escape this inhibition. By contrast, Omicron is sensitive to inhibition by GBP2/5, as well as inhibition by endosomal IFITM2 and IFITM3 consistent with Omicron’s use of alternative cell entry pathways. Our data show how VOC evolution under different selective pressures has influenced sensitivity to antiviral restriction factors, and thus, innate immunity.