Compared to the endemic HCoVs, SARS-CoV-2 infection results in the marked accumulation of 5′ end svRNAs and reaches higher levels at later stages of infection; the threshold for RIG-I activation can then be achieved by overcoming the antagonistic ability of viral defense proteins, which in turn drives exuberant IFN production and multiple ISGs. This evidence concerns the gene IFNA1 and infection.