biostudies-literatureBuck TKNIAID NIH HHSHHS | NIH | National Institute of Allergy and Infectious Diseasese0127822https://www.ebi.ac.uk/biostudies/studies/S-EPMC9426445biostudies-literatureUnknown13(4)Lassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the first to be identified, is particularly resistant to antibody neutralization. Lineage I LASV evades neutralization by half of known antibodies in the GPC-A antibody competition group and all but one of the antibodies in the GPC-B competition group. Here, we solve two cryo-electron microscopy (cryo-EM) structures of LI GP in complex with a GPC-A and a GPC-B antibody. We used complementary structural and biochemical techniques to identify single-amino-acid substitutions in LI that are responsible for immune evasion by each antibody group. Further, we show that LI infection is more dependent on the endosomal receptor lysosome-mBioNeutralizing Antibodies against Lassa Virus Lineage I.PMC9426445R21 AI137809U19 AI142790R01 AI141251T32 AI125179R01AI141251Li HHarkins SSZandonatti MAMoon-Walker ARobinson JEGarry RFBuck TKBranco LMHastie KMSchendel SLEnriquez ASSaphire EOfalseNeutralizing Antibodies against Lassa Virus Lineage I.Lassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the first to be identified, is particularly resistant to antibody neutralization. Lineage I LASV evades neutralization by half of known antibodies in the GPC-A antibody competition group and all but one of the antibodies in the GPC-B competition group. Here, we solve two cryo-electron microscopy (cryo-EM) structures of LI GP in complex with a GPC-A and a GPC-B antibody. We used complementary structural and biochemical techniques to identify single-amino-acid substitutions in LI that are responsible for immune evasion by each antibody group. Further, we show that LI infection is more dependent on the endosomal receptor lysosome-2022-01-01T00:00:00Z2022 Aug2026-06-13T06:03:42.717Z2025-02-19T03:28:59.031ZS-EPMC94264453573090410.1128/mbio.01278-22