The Low-Density Lipoprotein Receptor LDLR Mediates Cellular Entry of Nonenveloped Hepatitis A Virus

Why It Matters

Pinpointing LDLR as the nHAV receptor resolves a long‑standing debate and opens new avenues for antiviral strategies targeting viral entry. The finding also broadens our understanding of how diverse viruses exploit lipid‑receptor pathways.

Key Takeaways

• LDLR binds nHAV capsid near fivefold vertex, enabling endocytosis
• LDLR knockout blocks nHAV uptake but not eHAV, confirming specificity
• Soluble LDLR ectodomain and anti‑LDLR antibodies inhibit nHAV entry
• Cryo‑EM structure (1.7 Å) shows LDLR–VP1 interaction without capsid destabilization

Pulse Analysis

The discovery that LDLR serves as the entry receptor for naked hepatitis A virions settles a decade‑long controversy that pitted TIM1 against other candidates. By demonstrating that LDLR directly engages the capsid at the fivefold axis, the study clarifies why nHAV and its quasi‑enveloped counterpart follow distinct entry routes. This mechanistic clarity is crucial for virologists seeking to map host‑pathogen interactions and for public‑health officials aiming to improve vaccine design or develop entry‑blocking therapeutics.

Beyond hepatitis A, LDLR has emerged as a versatile portal for several RNA viruses, including alphaviruses and minor‑group rhinoviruses. The high‑resolution cryo‑EM structure reveals a flexible binding mode that does not disrupt capsid integrity, suggesting that LDLR can accommodate diverse viral surfaces while preserving its own ligand‑binding functions. The reliance on the LA repeats and EGF‑like domains mirrors how other pathogens co‑opt lipid‑receptor pathways, highlighting a convergent evolutionary strategy among unrelated viruses to hijack cholesterol‑regulating receptors for cell entry.

Clinically, targeting LDLR‑mediated uptake could provide a novel antiviral angle without compromising the receptor’s essential role in cholesterol homeostasis, especially if selective inhibitors or monoclonal antibodies block the virus‑specific interface. Moreover, the structural data (PDB 9TBH) offers a template for rational drug design and may inform broader research into picornavirus entry mechanisms. As hepatitis A remains a global health concern, these insights could accelerate the development of next‑generation prophylactics and therapeutic interventions.