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

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Most enveloped viruses utilize furin for glycoprotein maturation.
• Mammarenaviruses uniquely depend on host site-1 protease (S1P) for glycoprotein precursor (GPC) processing.
• The biological significance of S1P reliance in mammarenaviruses is not well understood.

Purpose of the Study:

• To investigate the role of S1P-mediated GPC processing in mammarenavirus pathogenesis.
• To characterize a furin-dependent recombinant lymphocytic choriomeningitis virus (LCMV) variant.
• To evaluate S1P as a potential antiviral target.

Main Methods:

• Generation of a furin-dependent LCMV variant (rCl13-RRRR).
• In vitro cell culture fitness assays.
• In vivo pathogenesis and persistence studies in immunocompetent mice.
• Analysis of viral clearance mechanisms (interferon, CD8+ T cells).
• Assessment of protective immunity post-infection.

Main Results:

• The furin-dependent rCl13-RRRR showed comparable cell culture fitness to the wild-type rCl13.
• rCl13-RRRR was significantly attenuated in vivo, failing to establish persistent infection.
• Viral clearance required interferon and CD8+ T cell responses.
• Immunization with rCl13-RRRR provided protection against lethal LCMV challenge.

Conclusions:

• S1P-mediated GPC processing is critical for mammarenavirus in vivo fitness and immune evasion.
• This unique viral processing mechanism highlights S1P as a druggable target for antiviral therapies.
• Host-directed strategies targeting S1P could combat pathogenic mammarenaviruses.