Infectious Entry and Neutralization of Pathogenic JC Polyomaviruses

Area of Science:

• Virology
• Neuroscience
• Immunology

Background:

• Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by JC polyomavirus (JCV) replication.
• JCV strains from PML patients have mutations affecting sialylated glycan receptor engagement for entry.
• Wild-type JCV is believed to use sialylated glycans for initial attachment and infection.

Purpose of the Study:

• To investigate alternative attachment mechanisms for JCV entry, particularly for PML-associated strains.
• To identify non-sialylated glycan receptors involved in JCV infection.
• To explore potential therapeutic targets for PML by understanding JCV entry pathways.

Main Methods:

• Analysis of JCV strains recovered from PML patients.
• Investigation of interactions between JCV variants and various glycan structures (sialylated and non-sialylated).
• Characterization of co-receptor engagement following initial attachment.
• Evaluation of monoclonal antibodies for their ability to block JCV infection.

Main Results:

• Non-sialylated glycosaminoglycans (GAGs) act as alternative attachment receptors for both wild-type and PML mutant JCV strains.
• PML mutant JCV strains utilize non-sialylated co-receptor glycans, such as asialo-GM1, after GAG attachment.
• JCV-neutralizing antibodies from recovered PML patients inhibit infection by blocking co-receptor glycan binding.

Conclusions:

• A GAG-dependent, sialylated glycan-independent pathway facilitates JCV entry.
• This alternative pathway is crucial for understanding JCV pathogenesis in PML.
• Targeting this pathway with inhibitors, including neutralizing antibodies, offers a promising strategy for PML treatment.