Structural basis for antibody-mediated neutralization of Lymphocytic choriomeningitis virus

Summary The mammarenavirus Lymphocytic choriomeningitis virus (LCMV) is a globally distributed zoonotic pathogen that can be lethal in immunocompromised patients and cause severe birth defects if acquired during pregnancy. Despite the fundamental importance of LCMV for studying immunobiology, the structure of the trimeric surface glycoprotein, essential for entry, vaccine design and antibody neutralization, remains unknown. In this study, we present the cryoEM structure of the LCMV surface glycoprotein (GP) in its trimeric prefusion assembly both alone and in complex with a rationally engineered monoclonal neutralizing antibody termed 18.5C-M28 (M28). Additionally, we show that passive administration of M28 protects mice from LCMV clone 13 (LCMV cl13 ) challenge when administered as either a prophylactic or therapeutic. Our study illuminates not only the overall structural organization of LCMV GP and the mechanism for its inhibition by M28, but also presents a promising therapeutic candidate to prevent severe or fatal disease in individuals who are at risk of infection by a virus that poses a threat worldwide. Highlights Rationally-engineered antibody M28 neutralizes lymphocytic choriomeningitis virus in vitro . First high-resolution cryoEM structure of the pre-fusion trimeric lymphocytic choriomeningitis virus glycoprotein alone and in complex with M28. M28 neutralizes by bridging adjacent glycoprotein protomers and locking it in the pre-fusion state. Prophylactic and therapeutic administration of M28 protects mice from chronic lymphocytic choriomeningitis virus infection.