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.
Zhou et al. (Sat,) studied this question.