Dataset Information

Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering.

ABSTRACT: Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizing ? and ? defensins from humans has demonstrated that the ?-defensin HD5 is effective at inhibiting the most common high-risk genotype, HPV16. A third class of defensin that has yet to be explored are ?-defensins: small, 18-amino acid cyclic peptides found in old-world monkeys whose unique structure makes them both highly cationic and resistant to degradation. Here we show that the prototype ?-defensin, rhesus theta defensin 1, inhibits hrHPV infection through a mechanism involving capsid clustering that inhibits virions from binding to cell surface receptor complexes.

SUBMITTER: Skeate JG

PROVIDER: S-EPMC7586039 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering.

Skeate Joseph G JG Segerink Wouter H WH Garcia Mauricio D MD Fernandez Daniel J DJ Prins Ruben R Lühen Kim P KP Voss Féline O FO Da Silva Diane M DM Kast W Martin WM

Frontiers in immunology 20200925

Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizi ...[more]

PMID: 33154746

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Project description:Papillomaviruses are a family of nonenveloped DNA viruses that infect the skin or mucosa of their vertebrate hosts. The viral life cycle is closely tied to the differentiation of infected keratinocytes. Papillomavirus virions are released into the environment through a process known as desquamation, in which keratinocytes lose structural integrity prior to being shed from the surface of the skin. During this process, virions are exposed to an increasingly oxidative environment, leading to their stabilization through the formation of disulfide cross-links between neighboring molecules of the major capsid protein, L1. We used time-lapse cryo-electron microscopy and image analysis to study the maturation of HPV16 capsids assembled in mammalian cells and exposed to an oxidizing environment after cell lysis. Initially, the virion is a loosely connected procapsid that, under in vitro conditions, condenses over several hours into the more familiar 60-nm-diameter papillomavirus capsid. In this process, the procapsid shrinks by ~5% in diameter, its pentameric capsomers change in structure (most markedly in the axial region), and the interaction surfaces between adjacent capsomers are consolidated. A C175S mutant that cannot achieve normal inter-L1 disulfide cross-links shows maturation-related shrinkage but does not achieve the fully condensed 60-nm form. Pseudoatomic modeling based on a 9-Å resolution reconstruction of fully mature capsids revealed C-terminal disulfide-stabilized "suspended bridges" that form intercapsomeric cross-links. The data suggest a model in which procapsids exist in a range of dynamic intermediates that can be locked into increasingly mature configurations by disulfide cross-linking, possibly through a Brownian ratchet mechanism. Importance: Human papillomaviruses (HPVs) cause nearly all cases of cervical cancer, a major fraction of cancers of the penis, vagina/vulva, anus, and tonsils, and genital and nongenital warts. HPV types associated with a high risk of cancer, such as HPV16, are generally transmitted via sexual contact. The nonenveloped virion of HPVs shows a high degree of stability, allowing the virus to persist in an infectious form in environmental fomites. In this study, we used cryo-electron microscopy to elucidate the structure of the HPV16 capsid at different stages of maturation. The fully mature capsid adopts a rigid, highly regular structure stabilized by intermolecular disulfide bonds. The availability of a pseudoatomic model of the fully mature HPV16 virion should help guide understanding of antibody responses elicited by HPV capsid-based vaccines.

Dataset Information

Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering.

Publications

Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering.

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