Architecture and evolution of viral complement evasion

The complement system constitutes a powerful antiviral defense, centered on C3b-mediated amplification that drives opsonization, inflammation, and membrane attack complex formation. To persist in the eukaryotic host, viruses must neutralize this amplification step, and strikingly diverse evolutionary lineages have converged on inhibiting C3b-mediated amplification. In this review, we compare host and viral regulators of complement activation (RCAs) to reveal the structural and mechanistic principles underlying C3b control. Human RCAs achieve complement regulation through modular assemblies of complement control protein domains whose multivalency, linker-encoded geometry, and domain-specific dynamics enable efficient decay acceleration and factor I cofactor activity. Viruses have independently replicated these principles through distinct evolutionary routes. Poxviruses and gammaherpesviruses acquired host-derived RCA genes via horizontal gene transfer, followed by lineage-specific refinement on extensively different time scales. In contrast, alphaherpesviruses evolved structurally unrelated complement inhibitors, exemplified by glycoprotein C, which suppresses C3b via a binding interface distinct from that used by RCAs. Despite profound structural divergence, most viral strategies converge on inhibition of the C3b amplification loop. This convergence highlights C3b suppression as an evolutionary bottleneck imposed by complement and reveals a fundamental asymmetry between structural innovation and functional constraint. Understanding how viruses repeatedly solve this invariant problem identifies complement regulation as a durable vulnerability and suggests therapeutic strategies resilient to viral diversity and mutation-driven escape.