Molecular mechanisms for broad neutralization of emerging RNA viruses

Abstract

Transmission of emerging RNA viruses from their zoonotic reservoirs into human populations poses a continuous threat to human health. The recent emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 underscores the critical importance of pandemic preparedness, which requires a basic understanding of mechanisms of viral pathogenesis to facilitate the rapid development of effective countermeasures. The first step of the virus life cycle involves attachment and entry into host cells. Neutralizing antibodies typically interfere with this step by engaging specific domains on viral spike proteins that attach to cell surface receptors. Here, we have isolated antigen-specific single B cells and identified monoclonal antibodies that target the receptor-binding subunits of two groups of emerging RNA viruses: coronaviruses and arenaviruses. For coronaviruses, we have identified a broadly neutralizing monoclonal antibody that competes with binding of the cellular receptor human angiotensin-converting enzyme 2 (ACE2). We also elucidated mechanisms by which the virus evades such antibodies, through structural plasticity of receptor contacts and acquisition of an N-linked glycan that sterically hinders access to the antibody epitope. For arenaviruses, we showed that a disulfide-stabilized motif is enriched in the CDR H3 loops of arenaviral hemorrhagic fever survivor-derived neutralizing antibodies, and that this motif allows the antibodies to mimic the viruses’ cellular receptor, human transferrin receptor 1 (hTfR1). Our studies highlight the evolutionary dynamics between receptor binding and antibody neutralization. Over time, emerging RNA viruses evolve under selective pressure to recognize receptors while evading neutralizing antibodies. However, the diverse repertoire of antibodies simultaneously allows them to overcome viral evolution by recognizing conserved structural determinants to directly or indirectly interfere with host cell binding. Our studies provide insight into basic mechanisms of antibody neutralization of emerging viruses, which may help to facilitate the development of broadly active countermeasures for the prevention and treatment of infection by these emerging pathogens.