Reframing clathrin-mediated viral entry: evidence standards, context dependence and host-directed vulnerabilities

Viral entry is the first obligatory step of productive infection and a rational point for host-directed antiviral intervention. This structured narrative review synthesizes evidence from database searches and citation tracking performed up to 18 June 2026. Clathrin-mediated endocytosis (CME) can internalize virus-receptor complexes and deliver them to endosomal compartments that support penetration, fusion, capsid remodeling, uncoating or genome release. However, CME should be interpreted as a series of experimentally separable checkpoints rather than as a single pathway label. Viral use of CME varies with strain, receptor and cofactor availability, host-cell type, membrane composition, protease environment, inoculum size and synchronization conditions. Strict CME-dependent entry is assigned only when direct perturbation of core or proximal CME machinery, supported by rescue or an orthogonal approach, converges with stage-resolved evidence of productive virion progression through clathrin/AP-2-positive coated pits or vesicles and an early functional entry readout in a defined virus-receptor-cell context. Pharmacological findings are treated as supportive rather than universally mandatory when stronger direct mechanistic evidence is available. The review integrates receptor organization, cargo-specific adaptor recruitment, membrane lipids, particle geometry, actin dynamics and virus-induced remodeling with a transparent evidence framework that distinguishes CME-associated, CME-involved and CME-dependent entry. It further separates mechanistic probes from host-directed strategies targeting membrane sphingolipids, TPC2-dependent endolysosomal trafficking, NPC1/cholesterol homeostasis, PIKfyve and kinase-regulated trafficking. Translational priorities are framed as context-dependent opportunities requiring target engagement, disease-relevant models and in vivo validation rather than as validated consequences of global CME blockade.