Replication competition between lactate dehydrogenase-elevating virus quasispecies in mice. Implications for...

Area of Science:

• Virology
• Immunology
• Evolutionary Biology

Background:

• Lactate dehydrogenase-elevating virus (LDV) quasispecies, LDV-P and LDV-vx, resist host immunity due to N-glycans on glycoprotein VP-3P.
• Laboratory mutants LDV-C and LDV-v lack N-glycans, increasing neuropathogenicity but also immune susceptibility.

Purpose of the Study:

• To assess the origins and evolution of LDV quasispecies by determining their competitiveness in mixed infections.
• To investigate the role of the humoral immune response and macrophage infection in LDV quasispecies dynamics.

Main Methods:

• Mixed infections of LDV quasispecies (LDV-P, LDV-vx, LDV-C, LDV-v) were established in various mouse models (wild type, SCID, nude, cyclophosphamide-treated).
• Competitive fitness was monitored using reverse transcription/polymerase chain reaction (RT-PCR) assays to distinguish between LDV strains.
• Replication fitness hierarchy was determined by analyzing the displacement of LDV strains in mixed infections.

Main Results:

• LDV-C and LDV-v were rapidly lost in mixed infections with LDV-P and LDV-vx, even when initially in excess.
• In immunocompetent mice, the humoral immune response accelerated the displacement of LDV-C and LDV-v by LDV-P and LDV-vx.
• LDV-C and LDV-v showed impaired competitive ability in infecting macrophages, with a fitness hierarchy observed: LDV-P/LDV-vx > LDV-v > LDV-C, independent of N-glycan number.

Conclusions:

• The humoral immune response significantly influences LDV quasispecies displacement.
• Replication fitness in macrophage infection is a critical factor in LDV quasispecies evolution, beyond immune evasion strategies.
• LDV-P and LDV-vx have achieved evolutionary stasis, demonstrating optimal fitness for persistent, immune-unimpeded viremic infections in mice.