Human papillomavirus capsids preferentially bind and infect tumor cells

Area of Science:

• Virology
• Oncology
• Biochemistry

Background:

• Human papillomavirus (HPV) virus-like particles (VLPs) and pseudovirions (PsV) do not infect intact cervicovaginal epithelium but bind to heparan sulfate proteoglycans (HSPG) on disrupted basement membranes.
• HPV capsids infect keratinocytes at disrupted sites, indicating a tropism for damaged epithelial tissues.

Purpose of the Study:

• To investigate the tropism of HPV capsids (VLP and PsV) for various disrupted epithelial and mesothelial tissues, as well as tumor-derived cell lines.
• To determine the role of heparan sulfate proteoglycans (HSPG) in HPV capsid binding and infection of tumor cells.
• To explore the potential of modified HPV capsids as diagnostic or therapeutic agents for cancer.

Main Methods:

• Testing HPV capsids (VLP and PsV) binding and infection on a variety of disrupted epithelial and mesothelial tissues.
• In vitro and in vivo studies using orthotopic models of human ovarian and lung cancer to assess tumor-specific properties of HPV capsids.
• Inhibition assays using heparin and ι-carrageenan, and surveys with modified heparins to elucidate the role of HSPG sulfation patterns in HPV binding.

Main Results:

• HPV capsids exhibit restricted tropism for disrupted epithelial and mesothelial tissues, while intact tissues remain resistant.
• HPV capsids directly bind and infect most tumor-derived cell lines in vitro and show tumor-specific properties in vivo.
• Tumor cell binding and infection are HSPG-dependent, with N-sulfation and O-6 sulfation of surface HSPG being crucial for HPV binding.

Conclusions:

• Tumor cells display HSPG modifications mimicking basement membrane patterns, which HPV capsids exploit for binding and infection.
• Modified HPV VLPs and/or PsV demonstrate potential as reagents for detecting and treating a broad spectrum of cancers.
• The findings highlight a novel strategy for targeted cancer therapy and diagnostics based on HPV capsid tropism.