Site-1 protease mediated GPC processing is required for persistence of LCMV Clone 13

Most enveloped viruses rely on furin for maturation of their surface glycoprotein. In contrast, mammarenaviruses process their glycoprotein precursor (GPC) using host site-1 protease (S1P), yet the biological implications of this unique reliance on S1P remain unclear. Here, we characterized a furin-dependent recombinant form (rCl13-RRRR) of the persistent clone 13 variant of LCMV (rCl13). Although rCl13-RRRR exhibited fitness comparable to rCl13 in cultured cells, it was highly attenuated in vivo and failed to establish persistence in immunocompetent mice. Clearance of rCl13-RRRR required interferon and CD8⁺ T cells, and immunization with rCl13-RRRR conferred protective immunity against a subsequent lethal LCMV challenge. Our results demonstrate that S1P-mediated processing of GPC is a key determinant of mammarenavirus fitness and immune evasion in vivo and highlight S1P as a promising and druggable target for host-directed antiviral strategies against human pathogenic mammarenaviruses.