The Old World arenavirus Lassa virus (LASV) is the etiologic agent of the often fatal Lassa hemorrhagic fever (LF). LASV is endemic to West Africa and exhibits a case fatality rate of greater than 50% in hospitalized patients and up to 90% in the third trimester of pregnancy. LASV is an enveloped, negative-stranded RNA virus with an ambisense, bisegmented genome that encodes the following four proteins: the matrix protein (Z), viral polymerase (L), nucleoprotein (NP), and glycoprotein precursor (GPC). GPC is trafficked from the endoplasmic reticulum (ER) through the compartment, where it is heavily N-glycosylated and undergoes processing by the cellular proteases SPase and SKI-1/S1P to produce the mature, prefusion glycoprotein (GP). Each GP monomer consists of the following three noncovalently associated subunits: the stable signal peptide (SSP), the receptor binding subunit (GP1), and the fusion machinery (GP2) (14, 15). Three GP monomers associate on the viral surface to form a trimer that drives viral attachment and cell entry.