Reframing clathrin-mediated viral entry: evidence standards, context dependence and host-directed vulnerabilities.
- 1Department of The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China.
- 2Department of AIDS Clinical Research Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
- 3School of Medicine, Henan University of Chinese Medicine, Zhengzhou, China.
Abstract
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.
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BibTeX
@article{wang2026reframing,
title = {{Reframing clathrin-mediated viral entry: evidence standards, context dependence and host-directed vulnerabilities.}},
author = {Qinying Wang and Liran Xu and Yangang Sun and Yuting Xia and Jingyu Yue},
journal = {Frontiers in cellular and infection microbiology},
year = {2026},
month = oct,
doi = {10.3389/fcimb.2026.1929024},
url = {https://europepmc.org/article/MED/42898937},
note = {CC BY},
}
RIS
TY - JOUR
TI - Reframing clathrin-mediated viral entry: evidence standards, context dependence and host-directed vulnerabilities.
AU - Qinying Wang
AU - Liran Xu
AU - Yangang Sun
AU - Yuting Xia
AU - Jingyu Yue
PY - 2026
DA - 2026/10/05
JO - Frontiers in cellular and infection microbiology
DO - 10.3389/fcimb.2026.1929024
UR - https://europepmc.org/article/MED/42898937
AB - 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.
SN - 2235-2988
ER -