Upping the ante: enhanced expression of interferon-antagonizing ORF6 and ORF9b proteins by SARS-CoV-2 variants of concern

SARS-CoV-2 exhibits a remarkable capability to subvert the host antiviral innate immune system. This adeptness is orchestrated by viral proteins, which initially attempt to obstruct the activation of the antiviral immune program and then act as a fail-safe mechanism to mitigate the downstream effects of the activated immune response. This dual strategy leads to delayed expression and enfeebled action of type-I and -III interferons at the infection site, enabling the virus to replicate extensively in the lungs and subsequently disseminate to other organs. Throughout the course of the COVID-19 pandemic, SARS-CoV-2 has undergone evolution, giving rise to several variants of concern, some with exceedingly higher transmission and virulence. These improved features have been linked, at least in part, to the heightened expression or activity of specific viral proteins involved in circumventing host defense mechanisms. In this review, we aim to provide a concise summary of two SARS-CoV-2 proteins, ORF6 and ORF9b, which provided selective advantage to certain variants, affecting their biology and pathogenesis.