Characterization of BST2-mediated restriction of SARS-CoV-2 and enhancement of Fc-mediated cellular responses 2097

Abstract Description BST2 is an antiviral factor that broadly restricts enveloped viruses by tethering nascent virions to the cell surface. Tethering also facilitates immune recognition as tethered virions are bound by antibodies, activating Fc receptors on NK cells and macrophages, leading to antibody dependent cellular cytotoxicity and phagocytosis (ADCC/P), respectively. We previously showed that SARS-CoV-2 is restricted by BST2. However, the virus evolved to use its Spike to downregulate this restriction factor. Interestingly, later variants of concern have enhanced abilities to downregulate BST2, such that they completely escape BST2’s restriction. Here, we interrogated (1) how Spike routes BST2 for degradation, and (2) how BST2 antagonism affects ADCC/P. I found that Spike interacts with BST2 and triggers its ubiquitination, leading to BST2 downregulation. Through protein mapping studies, I have identified the extracellular domain of Spike is responsible for downregulating BST2. Next, I demonstrated that the clathrin adaptor AP1 is required for downregulation of BST2. Finally, to test whether BST2 antagonism relieves pressure from antibody-mediated cellular responses, I developed assays to measure ADCC/P of SARS-CoV-2 infected cells. I have shown that BST2 enhances both ADCC and ADCP of SARS-CoV-2 infected cells. These data identify novel targets for antiviral design to block downregulation of BST2, and suggest a role for FC mediated responses in vaccine design. Funding Sources Work supported by T32AI007285 and URMC OP212320. Topic Categories Viral Immunology (VIR)