From mechanism to model: understanding intracellular positive-sense RNA virus replication through quantitative frameworks

Positive-sense single-stranded RNA viruses (+ssRNA) are major human pathogens,
including SARS-CoV-2, hepatitis C virus, and Dengue virus, posing enormous
global health burdens. Despite sharing genome type, +ssRNA viruses utilize
diverse replication strategies with highly variable dynamics. Mechanistic
modeling has proven invaluable for probing interactions underlying viral
replication and linking them to infection outcomes. Here we review mechanistic
models of pathogenic +ssRNA virus replication cycles and their contributions to
our understanding. We identify five key areas where models advanced knowledge:
genome allocation strategies across replication processes, host cell resource
exploitation, transcription regulation between viral RNA strands, virus-host
immune interactions, and therapeutic target identification. Models reveal +ssRNA
viruses face critical tradeoffs allocating genome between transcription,
translation, and assembly, with distinct strategies based on replication speed
and dissemination within and between host cells. Host factors, particularly
ribosomes and membrane structures, emerge as critical determinants of infection
outcomes. The interplay between viral antagonism and host innate immunity
significantly influences viral clearance, with interferon response timing and
magnitude being crucial. Across multiple virus types, targeting viral
translation and RNA synthesis is a potent aspect of innate immune response and
most effective for therapeutic intervention. We conclude mechanistic modeling
combined with experimental validation provides essential insights for
understanding +ssRNA virus biology critical for developing antiviral strategies.