# Filamentous virions act as non-infectious interfering particles to modulate papillomavirus infection

## TL;DR

This study shows that non-infectious filamentous particles from beta HPV5 modulate infection by acting as decoys, helping explain how these viruses bind to cells.

## Contribution

The study reveals that filamentous HPV5 particles interfere with infection by modulating binding to heparan sulfate proteoglycans.

## Key findings

- Filamentous HPV5 particles are non-infectious and interfere with initial infection by binding to heparan sulfate proteoglycans.
- Filamentous particles enhance infectious pseudovirion binding by acting as decoys for soluble glycosaminoglycans.
- Native HPV5 viruses in skin warts lack filamentous particles, suggesting differences in pseudovirion and native virus assembly.

## Abstract

Genus beta (β) human papillomaviruses (HPVs) potentially contribute to the development of non-melanoma skin cancer. Yet, comparatively little is known about their biology. In particular, details about initial infection, i.e., host cell entry, remain mostly elusive. During initial characterization of β HPV5 pseudovirion (PsV) preparations, surprisingly large amounts of filamentous particles were found besides the prototypical icosahedral (T = 7) virions. Whether these filamentous particles actively contribute to or interfere with infectivity of the spherical viruses is unknown. Using a combination of morphological, biochemical, and virological methods, we showed that the filamentous particles are non-infectious. Moreover, they interfered with the initial step of infection, i.e., binding to cellular heparan sulfate proteoglycans (HSPGs), and served as a decoy for soluble glycosaminoglycans, thereby modulating infectivity by enhancing infectious PsV binding. This explains previous seemingly contradictory findings on HPV5 binding to HSPGs. Importantly, in HPV5 skin warts from an immunocompromised patient, no filamentous particles were observable highlighting differences in the assembly of pseudovirions and native viruses.

Papillomaviruses contribute to numerous cancer incidents and significant mortality despite available vaccinations. Hence, high-risk α HPVs have been the focus of most research in the past. However, there are indications that less well-studied β HPVs may also contribute to certain malignancies. Little is known about their mode of cell invasion, and available data appear partially contradictory. Our work demonstrated that HPV5 as a model β HPVs yielded high amounts of non-infectious filamentous particles during PsV production. These acted as modulators of infection by the infectious spherical particles. Removing these filamentous particles showed that HPV5 engaged HSPGs as the primary receptor for cell binding, similar to high-risk α HPV, indicating a conserved feature not only among α, but also among β HPVs, thereby explaining previous contradictions.