BST-2/tTetherin is an interferon-stimulated gene that restricts enveloped viruses by tethering nascent virions at the plasma membrane. Because virions tethered at the cell surface serve as potent antigens for immune recognition, we hypothesized that BST-2 plays additional roles in antiviral immunity by enabling antibody opsonization of tethered particles and promoting the subsequent engagement of Fcγ receptors on natural killer cells and phagocytes to trigger antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Consistent with this hypothesis, we found that BST-2 restricts SARS-CoV-2 egress and that BST-2-mediated virion tethering enhances ADCC and ADCP of infected cells. However, SARS-CoV-2 uses Spike to counteract BST-2 through a physical interaction that causes the lysosomal degradation of BST-2. Remarkably, variants of concern (VOC) exhibit enhanced BST-2 antagonism compared to ancestral strains due to mutations in their Spike that increase Spike-BST-2 binding, thereby promoting more efficient BST-2 downregulation and protection from BST-2-dependent Fc-mediated responses. Hence, our findings indicate that BST-2 antagonism represents a selective pressure shaping the evolution of SARS-CoV-2.

Because ADCC and ADCP are key processes for clearing viral infections, we tested a BST2-like factor (art-tetherin) composed of domains from different proteins that recapitulate BST-2’s topology, subcellular distribution and virion-tethering activity, while diverging at the primary sequence so viruses cannot antagonize art-tetherin. art-tetherin restricted virion release across ancestral and recent strains with comparable efficiency and reinstated the susceptibility of VOC-infected cells to ADCC and ADCP.

Collectively, these data establish BST-2 as a link between innate and adaptive immunity that exerts evolutionary pressure on SARS-CoV-2. Furthermore, our findings indicate that viral escape from BST-2 can be circumvented via synthetic tethering or by disabling Spike-mediated BST-2 downregulation. Hence, our results support that developing interventions to promote virion tethering will enhance immune clearance of SARS-CoV-2-infected cells across current and future VOC.