Receptor binding and antibody neutralization of emerging RNA viruses

Abstract

The spillover of viral zoonotic pathogens into human populations is an ever present threat to public health. Preparedness for the threat of emerging viruses requires an understanding of viral pathogenesis and the development of effective treatments. Viral attachment and entry into host cells is the first critical step in viral infection. This step is the target of neutralizing antibodies that recognize viral receptor binding subunits to block infectivity. Here we use single B cell cloning to isolate monoclonal antibodies that target the receptor-binding subunits of two groups of emerging enveloped RNA viruses – arenaviruses and coronaviruses. For arenaviruses, we identify a key cross-neutralizing epitope in the receptor-binding subunit (GP1) of Junin virus and Machupo virus. For coronaviruses, we identify a critical neutralizing epitope on the S1 receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein and define pathways for neutralization escape while retaining receptor-binding activity. Alphaviruses are a group of less well studied emerging RNA viruses. We identify lipoprotein receptors as a novel class of evolutionarily conserved cellular receptors for encephalitic alphaviruses. Our work sets the stage for studies examining, in detail, the relationship between antibody neutralization and receptor-binding, which in turn may help inform the development of effective antiviral monoclonal antibodies.