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

  • Npj Viruses. 2026 Mar 14;4(1):18. doi: 10.1038/s44298-026-00184-7.
Ruifeng Zhou  1 ,  Haydar Witwit  1 ,  Tingting Ai  1 ,  Maheeka Bimal  1 ,  Rachel Y Sattler  1 ,  Kristi L Marquardt  1 ,  Beatrice Cubitt  1 ,  Arthur S Kim  1  2 ,  John R Teijaro  3 ,  Juan Carlos de la Torre  4
Affiliations
  • 1. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
  • 2. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 3. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
  • 4. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
PMID: 41826412 DOI: 10.1038/s44298-026-00184-7
Abstract

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.

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