Maturation of the Human Papillomavirus 16 Capsid

ABSTRACT 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 desq...

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Autores principales:	Giovanni Cardone, Adam L. Moyer, Naiqian Cheng, Cynthia D. Thompson, Israel Dvoretzky, Douglas R. Lowy, John T. Schiller, Alasdair C. Steven, Christopher B. Buck, Benes L. Trus
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4faabef3fe0f4cb8b7adc6398e41ad9f
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spelling	oai:doaj.org-article:4faabef3fe0f4cb8b7adc6398e41ad9f2021-11-15T15:47:22ZMaturation of the Human Papillomavirus 16 Capsid10.1128/mBio.01104-142150-7511https://doaj.org/article/4faabef3fe0f4cb8b7adc6398e41ad9f2014-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01104-14https://doaj.org/toc/2150-7511ABSTRACT 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.Giovanni CardoneAdam L. MoyerNaiqian ChengCynthia D. ThompsonIsrael DvoretzkyDouglas R. LowyJohn T. SchillerAlasdair C. StevenChristopher B. BuckBenes L. TrusAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 4 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Giovanni Cardone Adam L. Moyer Naiqian Cheng Cynthia D. Thompson Israel Dvoretzky Douglas R. Lowy John T. Schiller Alasdair C. Steven Christopher B. Buck Benes L. Trus Maturation of the Human Papillomavirus 16 Capsid
description	ABSTRACT 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.
format	article
author	Giovanni Cardone Adam L. Moyer Naiqian Cheng Cynthia D. Thompson Israel Dvoretzky Douglas R. Lowy John T. Schiller Alasdair C. Steven Christopher B. Buck Benes L. Trus
author_facet	Giovanni Cardone Adam L. Moyer Naiqian Cheng Cynthia D. Thompson Israel Dvoretzky Douglas R. Lowy John T. Schiller Alasdair C. Steven Christopher B. Buck Benes L. Trus
author_sort	Giovanni Cardone
title	Maturation of the Human Papillomavirus 16 Capsid
title_short	Maturation of the Human Papillomavirus 16 Capsid
title_full	Maturation of the Human Papillomavirus 16 Capsid
title_fullStr	Maturation of the Human Papillomavirus 16 Capsid
title_full_unstemmed	Maturation of the Human Papillomavirus 16 Capsid
title_sort	maturation of the human papillomavirus 16 capsid
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/4faabef3fe0f4cb8b7adc6398e41ad9f
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Maturation of the Human Papillomavirus 16 Capsid

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