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Open AccessEditorial

Expert Views on HPV Infection

by Alison A. McBride and Karl Münger

Viruses 2018, 10(2), 94; https://doi.org/10.3390/v10020094 - 24 Feb 2018

Cited by 17 | Viewed by 4850

Abstract

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(This article belongs to the Special Issue Expert Views on HPV Infection)

Research

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Open AccessArticle

The Enigmatic Origin of Papillomavirus Protein Domains

by Mikk Puustusmaa, Heleri Kirsip, Kevin Gaston and Aare Abroi

Viruses 2017, 9(9), 240; https://doi.org/10.3390/v9090240 - 23 Aug 2017

Cited by 6 | Viewed by 7239

Abstract

Almost a century has passed since the discovery of papillomaviruses. A few decades of research have given a wealth of information on the molecular biology of papillomaviruses. Several excellent studies have been performed looking at the long- and short-term evolution of these viruses. [...] Read more.

Almost a century has passed since the discovery of papillomaviruses. A few decades of research have given a wealth of information on the molecular biology of papillomaviruses. Several excellent studies have been performed looking at the long- and short-term evolution of these viruses. However, when and how papillomaviruses originate is still a mystery. In this study, we systematically searched the (sequenced) biosphere to find distant homologs of papillomaviral protein domains. Our data show that, even including structural information, which allows us to find deeper evolutionary relationships compared to sequence-only based methods, only half of the protein domains in papillomaviruses have relatives in the rest of the biosphere. We show that the major capsid protein L1 and the replication protein E1 have relatives in several viral families, sharing three protein domains with Polyomaviridae and Parvoviridae. However, only the E1 replication protein has connections with cellular organisms. Most likely, the papillomavirus ancestor is of marine origin, a biotope that is not very well sequenced at the present time. Nevertheless, there is no evidence as to how papillomaviruses originated and how they became vertebrate and epithelium specific. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessCommunication

Molecular Mechanisms of Human Papillomavirus Induced Skin Carcinogenesis

by Martin Hufbauer and Baki Akgül

Viruses 2017, 9(7), 187; https://doi.org/10.3390/v9070187 - 14 Jul 2017

Cited by 55 | Viewed by 12618

Abstract

Infection of the cutaneous skin with human papillomaviruses (HPV) of genus betapapillomavirus (βHPV) is associated with the development of premalignant actinic keratoses and squamous cell carcinoma. Due to the higher viral loads of βHPVs in actinic keratoses than in cancerous lesions, it is [...] Read more.

Infection of the cutaneous skin with human papillomaviruses (HPV) of genus betapapillomavirus (βHPV) is associated with the development of premalignant actinic keratoses and squamous cell carcinoma. Due to the higher viral loads of βHPVs in actinic keratoses than in cancerous lesions, it is currently discussed that these viruses play a carcinogenic role in cancer initiation. In vitro assays performed to characterize the cell transforming activities of high-risk HPV types of genus alphapapillomavirus have markedly contributed to the present knowledge on their oncogenic functions. However, these assays failed to detect oncogenic functions of βHPV early proteins. They were not suitable for investigations aiming to study the interactive role of βHPV positive epidermis with mesenchymal cells and the extracellular matrix. This review focuses on βHPV gene functions with special focus on oncogenic mechanisms that may be relevant for skin cancer development. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Review

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15 pages, 344 KiB

Open AccessReview

Risk of Human Papillomavirus Infection in Cancer-Prone Individuals: What We Know

by Ruby Khoury, Sharon Sauter, Melinda Butsch Kovacic, Adam S. Nelson, Kasiani C. Myers, Parinda A. Mehta, Stella M. Davies and Susanne I. Wells

Viruses 2018, 10(1), 47; https://doi.org/10.3390/v10010047 - 20 Jan 2018

Cited by 16 | Viewed by 6086

Abstract

Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have [...] Read more.

Human papillomavirus (HPV) infections cause a significant proportion of cancers worldwide, predominantly squamous cell carcinomas (SCC) of the mucosas and skin. High-risk HPV types are associated with SCCs of the anogenital and oropharyngeal tract. HPV oncogene activities and the biology of SCCs have been intensely studied in laboratory models and humans. What remains largely unknown are host tissue and immune-related factors that determine an individual’s susceptibility to infection and/or carcinogenesis. Such susceptibility factors could serve to identify those at greatest risk and spark individually tailored HPV and SCC prevention efforts. Fanconi anemia (FA) is an inherited DNA repair disorder that is in part characterized by extreme susceptibility to SCCs. An increased prevalence of HPV has been reported in affected individuals, and molecular and functional connections between FA, SCC, and HPV were established in laboratory models. However, the presence of HPV in some human FA tumors is controversial, and the extent of the etiological connections remains to be established. Herein, we discuss cellular, immunological, and phenotypic features of FA, placed into the context of HPV pathogenesis. The goal is to highlight this orphan disease as a unique model system to uncover host genetic and molecular HPV features, as well as SCC susceptibility factors. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Structural Insights in Multifunctional Papillomavirus Oncoproteins

by Irina Suarez and Gilles Trave

Viruses 2018, 10(1), 37; https://doi.org/10.3390/v10010037 - 15 Jan 2018

Cited by 30 | Viewed by 6706

Abstract

Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the last decade a wealth of three-dimensional information has been gained on both proteins whether free or complexed to host target [...] Read more.

Since their discovery in the mid-eighties, the main papillomavirus oncoproteins E6 and E7 have been recalcitrant to high-resolution structure analysis. However, in the last decade a wealth of three-dimensional information has been gained on both proteins whether free or complexed to host target proteins. Here, we first summarize the diverse activities of these small multifunctional oncoproteins. Next, we review the available structural data and the new insights they provide about the evolution of E6 and E7, their multiple interactions and their functional variability across human papillomavirus (HPV) species. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Subcellular Trafficking of the Papillomavirus Genome during Initial Infection: The Remarkable Abilities of Minor Capsid Protein L2

by Samuel K. Campos

Viruses 2017, 9(12), 370; https://doi.org/10.3390/v9120370 - 3 Dec 2017

Cited by 44 | Viewed by 9368

Abstract

Since 2012, our understanding of human papillomavirus (HPV) subcellular trafficking has undergone a drastic paradigm shift. Work from multiple laboratories has revealed that HPV has evolved a unique means to deliver its viral genome (vDNA) to the cell nucleus, relying on myriad host [...] Read more.

Since 2012, our understanding of human papillomavirus (HPV) subcellular trafficking has undergone a drastic paradigm shift. Work from multiple laboratories has revealed that HPV has evolved a unique means to deliver its viral genome (vDNA) to the cell nucleus, relying on myriad host cell proteins and processes. The major breakthrough finding from these recent endeavors has been the realization of L2-dependent utilization of cellular sorting factors for the retrograde transport of vDNA away from degradative endo/lysosomal compartments to the Golgi, prior to mitosis-dependent nuclear accumulation of L2/vDNA. An overview of current models of HPV entry, subcellular trafficking, and the role of L2 during initial infection is provided below, highlighting unresolved questions and gaps in knowledge. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Why Human Papillomavirus Acute Infections Matter

by Samuel Alizon, Carmen Lía Murall and Ignacio G. Bravo

Viruses 2017, 9(10), 293; https://doi.org/10.3390/v9100293 - 10 Oct 2017

Cited by 45 | Viewed by 11116

Abstract

Most infections by human papillomaviruses (HPVs) are `acute’, that is non-persistent. Yet, for HPVs, as for many other oncoviruses, there is a striking gap between our detailed understanding of chronic infections and our limited data on the early stages of infection. Here we [...] Read more.

Most infections by human papillomaviruses (HPVs) are `acute’, that is non-persistent. Yet, for HPVs, as for many other oncoviruses, there is a striking gap between our detailed understanding of chronic infections and our limited data on the early stages of infection. Here we argue that studying HPV acute infections is necessary and timely. Focusing on early interactions will help explain why certain infections are cleared while others become chronic or latent. From a molecular perspective, descriptions of immune effectors and pro-inflammatory pathways during the initial stages of infections have the potential to lead to novel treatments or to improved handling algorithms. From a dynamical perspective, adopting concepts from spatial ecology, such as meta-populations or meta-communities, can help explain why HPV acute infections sometimes last for years. Furthermore, cervical cancer screening and vaccines impose novel iatrogenic pressures on HPVs, implying that anticipating any viral evolutionary response remains essential. Finally, hints at the associations between HPV acute infections and fertility deserve further investigation given their high, worldwide prevalence. Overall, understanding asymptomatic and benign infections may be instrumental in reducing HPV virulence. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Natural History of HPV Infection across the Lifespan: Role of Viral Latency

by Patti E. Gravitt and Rachel L. Winer

Viruses 2017, 9(10), 267; https://doi.org/10.3390/v9100267 - 21 Sep 2017

Cited by 161 | Viewed by 22058

Abstract

Large-scale epidemiologic studies have been invaluable for elaboration of the causal relationship between persistent detection of genital human papillomavirus (HPV) infection and the development of invasive cervical cancer. However, these studies provide limited data to adequately inform models of the individual-level natural history [...] Read more.

Large-scale epidemiologic studies have been invaluable for elaboration of the causal relationship between persistent detection of genital human papillomavirus (HPV) infection and the development of invasive cervical cancer. However, these studies provide limited data to adequately inform models of the individual-level natural history of HPV infection over the course of a lifetime, and particularly ignore the biological distinction between HPV-negative tests and lack of infection (i.e., the possibility of latent, undetectable HPV infection). Using data from more recent epidemiological studies, this review proposes an alternative model of the natural history of genital HPV across the life span. We argue that a more complete elucidation of the age-specific probabilities of the alternative transitions is highly relevant with the expanded use of HPV testing in cervical cancer screening. With routine HPV testing in cervical cancer screening, women commonly transition in and out of HPV detectability, raising concerns for the patient and the provider regarding the source of the positive test result, its prognosis, and effective strategies to prevent future recurrence. Alternative study designs and analytic frameworks are proposed to better understand the frequency and determinants of these transition pathways. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Mechanisms by which HPV Induces a Replication Competent Environment in Differentiating Keratinocytes

by Cary Moody

Viruses 2017, 9(9), 261; https://doi.org/10.3390/v9090261 - 19 Sep 2017

Cited by 63 | Viewed by 14218

Abstract

Human papillomaviruses (HPV) are the causative agents of cervical cancer and are also associated with other genital malignancies, as well as an increasing number of head and neck cancers. HPVs have evolved their life cycle to contend with the different cell states found [...] Read more.

Human papillomaviruses (HPV) are the causative agents of cervical cancer and are also associated with other genital malignancies, as well as an increasing number of head and neck cancers. HPVs have evolved their life cycle to contend with the different cell states found in the stratified epithelium. Initial infection and viral genome maintenance occurs in the proliferating basal cells of the stratified epithelium, where cellular replication machinery is abundant. However, the productive phase of the viral life cycle, including productive replication, late gene expression and virion production, occurs upon epithelial differentiation, in cells that normally exit the cell cycle. This review outlines how HPV interfaces with specific cellular signaling pathways and factors to provide a replication-competent environment in differentiating cells. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Immunopathogenesis of HPV-Associated Cancers and Prospects for Immunotherapy

by Sigrun Smola

Viruses 2017, 9(9), 254; https://doi.org/10.3390/v9090254 - 12 Sep 2017

Cited by 105 | Viewed by 16182

Abstract

Human papillomavirus (HPV) infection is a causative factor for various cancers of the anogenital region and oropharynx, and is supposed to play an important cofactor role for skin carcinogenesis. Evasion from immunosurveillance favors viral persistence. However, there is evidence that the mere presence [...] Read more.

Human papillomavirus (HPV) infection is a causative factor for various cancers of the anogenital region and oropharynx, and is supposed to play an important cofactor role for skin carcinogenesis. Evasion from immunosurveillance favors viral persistence. However, there is evidence that the mere presence of oncogenic HPV is not sufficient for malignant progression and that additional tumor-promoting steps are required. Recent studies have demonstrated that HPV-transformed cells actively promote chronic stromal inflammation and conspire with cells in the local microenvironment to promote carcinogenesis. This review highlights the complex interplay between HPV-infected cells and the local immune microenvironment during oncogenic HPV infection, persistence, and malignant progression, and discusses new prospects for diagnosis and immunotherapy of HPV-associated cancers. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Epigenetic Alterations in Human Papillomavirus-Associated Cancers

by David Soto, Christine Song and Margaret E. McLaughlin-Drubin

Viruses 2017, 9(9), 248; https://doi.org/10.3390/v9090248 - 1 Sep 2017

Cited by 73 | Viewed by 8732

Abstract

Approximately 15–20% of human cancers are caused by viruses, including human papillomaviruses (HPVs). Viruses are obligatory intracellular parasites and encode proteins that reprogram the regulatory networks governing host cellular signaling pathways that control recognition by the immune system, proliferation, differentiation, genomic integrity, and [...] Read more.

Approximately 15–20% of human cancers are caused by viruses, including human papillomaviruses (HPVs). Viruses are obligatory intracellular parasites and encode proteins that reprogram the regulatory networks governing host cellular signaling pathways that control recognition by the immune system, proliferation, differentiation, genomic integrity, and cell death. Given that key proteins in these regulatory networks are also subject to mutation in non-virally associated diseases and cancers, the study of oncogenic viruses has also been instrumental to the discovery and analysis of many fundamental cellular processes, including messenger RNA (mRNA) splicing, transcriptional enhancers, oncogenes and tumor suppressors, signal transduction, immune regulation, and cell cycle control. More recently, tumor viruses, in particular HPV, have proven themselves invaluable in the study of the cancer epigenome. Epigenetic silencing or de-silencing of genes can have cellular consequences that are akin to genetic mutations, i.e., the loss and gain of expression of genes that are not usually expressed in a certain cell type and/or genes that have tumor suppressive or oncogenic activities, respectively. Unlike genetic mutations, the reversible nature of epigenetic modifications affords an opportunity of epigenetic therapy for cancer. This review summarizes the current knowledge on epigenetic regulation in HPV-infected cells with a focus on those elements with relevance to carcinogenesis. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

The Mouse Papillomavirus Infection Model

by Jiafen Hu, Nancy M. Cladel, Lynn R. Budgeon, Karla K. Balogh and Neil D. Christensen

Viruses 2017, 9(9), 246; https://doi.org/10.3390/v9090246 - 30 Aug 2017

Cited by 38 | Viewed by 9176

Abstract

The mouse papillomavirus (MmuPV1) was first reported in 2011 and has since become a powerful research tool. Through collective efforts from different groups, significant progress has been made in the understanding of molecular, virological, and immunological mechanisms of MmuPV1 infections in both immunocompromised [...] Read more.

The mouse papillomavirus (MmuPV1) was first reported in 2011 and has since become a powerful research tool. Through collective efforts from different groups, significant progress has been made in the understanding of molecular, virological, and immunological mechanisms of MmuPV1 infections in both immunocompromised and immunocompetent hosts. This mouse papillomavirus provides, for the first time, the opportunity to study papillomavirus infections in the context of a small common laboratory animal for which abundant reagents are available and for which many strains exist. The model is a major step forward in the study of papillomavirus disease and pathology. In this review, we summarize studies using MmuPV1 over the past six years and share our perspectives on the value of this unique model system. Specifically, we discuss viral pathogenesis in cutaneous and mucosal tissues as well as in different mouse strains, immune responses to the virus, and local host-restricted factors that may be involved in MmuPV1 infections and associated disease progression. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Keratinocyte Differentiation-Dependent Human Papillomavirus Gene Regulation

by Sheila V. Graham

Viruses 2017, 9(9), 245; https://doi.org/10.3390/v9090245 - 30 Aug 2017

Cited by 77 | Viewed by 11647

Abstract

Human papillomaviruses (HPVs) cause diseases ranging from benign warts to invasive cancers. HPVs infect epithelial cells and their replication cycle is tightly linked with the differentiation process of the infected keratinocyte. The normal replication cycle involves an early and a late phase. The [...] Read more.

Human papillomaviruses (HPVs) cause diseases ranging from benign warts to invasive cancers. HPVs infect epithelial cells and their replication cycle is tightly linked with the differentiation process of the infected keratinocyte. The normal replication cycle involves an early and a late phase. The early phase encompasses viral entry and initial genome replication, stimulation of cell division and inhibition of apoptosis in the infected cell. Late events in the HPV life cycle include viral genome amplification, virion formation, and release into the environment from the surface of the epithelium. The main proteins required at the late stage of infection for viral genome amplification include E1, E2, E4 and E5. The late proteins L1 and L2 are structural proteins that form the viral capsid. Regulation of these late events involves both cellular and viral proteins. The late viral mRNAs are expressed from a specific late promoter but final late mRNA levels in the infected cell are controlled by splicing, polyadenylation, nuclear export and RNA stability. Viral late protein expression is also controlled at the level of translation. This review will discuss current knowledge of how HPV late gene expression is regulated. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Roles of APOBEC3A and APOBEC3B in Human Papillomavirus Infection and Disease Progression

by Cody J. Warren, Joseph A. Westrich, Koenraad Van Doorslaer and Dohun Pyeon

Viruses 2017, 9(8), 233; https://doi.org/10.3390/v9080233 - 21 Aug 2017

Cited by 78 | Viewed by 18502

Abstract

The apolipoprotein B messenger RNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) family of cytidine deaminases plays an important role in the innate immune response to viral infections by editing viral genomes. However, the cytidine deaminase activity of APOBEC3 enzymes also induces somatic mutations in host [...] Read more.

The apolipoprotein B messenger RNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) family of cytidine deaminases plays an important role in the innate immune response to viral infections by editing viral genomes. However, the cytidine deaminase activity of APOBEC3 enzymes also induces somatic mutations in host genomes, which may drive cancer progression. Recent studies of human papillomavirus (HPV) infection and disease outcome highlight this duality. HPV infection is potently inhibited by one family member, APOBEC3A. Expression of APOBEC3A and APOBEC3B is highly elevated by the HPV oncoproteins E6 and E7 during persistent virus infection and disease progression. Furthermore, there is a high prevalence of APOBEC3A and APOBEC3B mutation signatures in HPV-associated cancers. These findings suggest that induction of an APOBEC3-mediated antiviral response during HPV infection may inadvertently contribute to cancer mutagenesis and virus evolution. Here, we discuss current understanding of APOBEC3A and APOBEC3B biology in HPV restriction, evolution, and associated cancer mutagenesis. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Targeting Persistent Human Papillomavirus Infection

by Srinidhi Shanmugasundaram and Jianxin You

Viruses 2017, 9(8), 229; https://doi.org/10.3390/v9080229 - 18 Aug 2017

Cited by 125 | Viewed by 26748

Abstract

While the majority of Human papillomavirus (HPV) infections are transient and cleared within a couple of years following exposure, 10–20% of infections persist latently, leading to disease progression and, ultimately, various forms of invasive cancer. Despite the clinical efficiency of recently developed multivalent [...] Read more.

While the majority of Human papillomavirus (HPV) infections are transient and cleared within a couple of years following exposure, 10–20% of infections persist latently, leading to disease progression and, ultimately, various forms of invasive cancer. Despite the clinical efficiency of recently developed multivalent prophylactic HPV vaccines, these preventive measures are not effective against pre-existing infection. Additionally, considering that the burden associated with HPV is greatest in regions with limited access to preventative vaccination, the development of effective therapies targeting persistent infection remains imperative. This review discusses not only the mechanisms underlying persistent HPV infection, but also the promise of immunomodulatory therapeutic vaccines and small-molecular inhibitors, which aim to augment the host immune response against the viral infection as well as obstruct critical viral–host interactions. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Changing Stem Cell Dynamics during Papillomavirus Infection: Potential Roles for Cellular Plasticity in the Viral Lifecycle and Disease

by Katerina Strati

Viruses 2017, 9(8), 221; https://doi.org/10.3390/v9080221 - 12 Aug 2017

Cited by 14 | Viewed by 5283

Abstract

Stem cells and cellular plasticity are likely important components of tissue response to infection. There is emerging evidence that stem cells harbor receptors for common pathogen motifs and that they are receptive to local inflammatory signals in ways suggesting that they are critical [...] Read more.

Stem cells and cellular plasticity are likely important components of tissue response to infection. There is emerging evidence that stem cells harbor receptors for common pathogen motifs and that they are receptive to local inflammatory signals in ways suggesting that they are critical responders that determine the balance between health and disease. In the field of papillomaviruses stem cells have been speculated to play roles during the viral life cycle, particularly during maintenance, and virus-promoted carcinogenesis but little has been conclusively determined. I summarize here evidence that gives clues to the potential role of stem cells and cellular plasticity in the lifecycle papillomavirus and linked carcinogenesis. I also discuss outstanding questions which need to be resolved. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Human Papillomavirus and the Stroma: Bidirectional Crosstalk during the Virus Life Cycle and Carcinogenesis

by Megan E. Spurgeon and Paul F. Lambert

Viruses 2017, 9(8), 219; https://doi.org/10.3390/v9080219 - 9 Aug 2017

Cited by 49 | Viewed by 17145

Abstract

Human papillomaviruses (HPVs) are double-stranded DNA (dsDNA) tumor viruses that are causally associated with human cancers of the anogenital tract, skin, and oral cavity. Despite the availability of prophylactic vaccines, HPVs remain a major global health issue due to inadequate vaccine availability and [...] Read more.

Human papillomaviruses (HPVs) are double-stranded DNA (dsDNA) tumor viruses that are causally associated with human cancers of the anogenital tract, skin, and oral cavity. Despite the availability of prophylactic vaccines, HPVs remain a major global health issue due to inadequate vaccine availability and vaccination coverage. The HPV life cycle is established and completed in the terminally differentiating stratified epithelia, and decades of research using in vitro organotypic raft cultures and in vivo genetically engineered mouse models have contributed to our understanding of the interactions between HPVs and the epithelium. More recently, important and emerging roles for the underlying stroma, or microenvironment, during the HPV life cycle and HPV-induced disease have become clear. This review discusses the current understanding of the bidirectional communication and relationship between HPV-infected epithelia and the surrounding microenvironment. As is the case with other human cancers, evidence suggests that the stroma functions as a significant partner in tumorigenesis and helps facilitate the oncogenic potential of HPVs in the stratified epithelium. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Exosomes and Other Extracellular Vesicles in HPV Transmission and Carcinogenesis

by David Guenat, François Hermetet, Jean-Luc Prétet and Christiane Mougin

Viruses 2017, 9(8), 211; https://doi.org/10.3390/v9080211 - 7 Aug 2017

Cited by 56 | Viewed by 10023

Abstract

Extracellular vesicles (EVs), including exosomes (Exos), microvesicles (MVs) and apoptotic bodies (ABs) are released in biofluids by virtually all living cells. Tumor-derived Exos and MVs are garnering increasing attention because of their ability to participate in cellular communication or transfer of bioactive molecules [...] Read more.

Extracellular vesicles (EVs), including exosomes (Exos), microvesicles (MVs) and apoptotic bodies (ABs) are released in biofluids by virtually all living cells. Tumor-derived Exos and MVs are garnering increasing attention because of their ability to participate in cellular communication or transfer of bioactive molecules (mRNAs, microRNAs, DNA and proteins) between neighboring cancerous or normal cells, and to contribute to human cancer progression. Malignant traits can also be transferred from apoptotic cancer cells to phagocytizing cells, either professional or non-professional. In this review, we focus on Exos and ABs and their relationship with human papillomavirus (HPV)-associated tumor development. The potential implication of EVs as theranostic biomarkers is also addressed. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Integration of Human Papillomavirus Genomes in Head and Neck Cancer: Is It Time to Consider a Paradigm Shift?

by Iain M. Morgan, Laurence J. DiNardo and Brad Windle

Viruses 2017, 9(8), 208; https://doi.org/10.3390/v9080208 - 3 Aug 2017

Cited by 44 | Viewed by 9937

Abstract

Human papillomaviruses (HPV) are detected in 70–80% of oropharyngeal cancers in the developed world, the incidence of which has reached epidemic proportions. The current paradigm regarding the status of the viral genome in these cancers is that there are three situations: one where [...] Read more.

Human papillomaviruses (HPV) are detected in 70–80% of oropharyngeal cancers in the developed world, the incidence of which has reached epidemic proportions. The current paradigm regarding the status of the viral genome in these cancers is that there are three situations: one where the viral genome remains episomal, one where the viral genome integrates into the host genome and a third where there is a mixture of both integrated and episomal HPV genomes. Our recent work suggests that this third category has been mischaracterized as having integrated HPV genomes; evidence indicates that this category consists of virus–human hybrid episomes. Most of these hybrid episomes are consistent with being maintained by replication from HPV origin. We discuss our evidence to support this new paradigm, how such genomes can arise, and more importantly the implications for the clinical management of HPV positive head and neck cancers following accurate determination of the viral genome status. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Somatic Host Cell Alterations in HPV Carcinogenesis

by Tamara R. Litwin, Megan A. Clarke, Michael Dean and Nicolas Wentzensen

Viruses 2017, 9(8), 206; https://doi.org/10.3390/v9080206 - 3 Aug 2017

Cited by 59 | Viewed by 11426

Abstract

High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells [...] Read more.

High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells for malignant transformation. HPV-driven cancers share characteristic somatic changes, including apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-driven mutations and genomic instability leading to copy number variations and large chromosomal rearrangements. HPV-associated cancers have recurrent somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and phosphatase and tensin homolog (PTEN), human leukocyte antigen A and B (HLA-A and HLA-B)-A/B, and the transforming growth factor beta (TGFβ) pathway, and rarely have mutations in the tumor protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) tumor suppressor genes. There are some variations by tumor site, such as NOTCH1 mutations which are primarily found in head and neck cancers. Understanding the somatic events following HPV infection and persistence can aid the development of early detection biomarkers, particularly when mutations in precancers are characterized. Somatic mutations may also influence prognosis and treatment decisions. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Telomerase Induction in HPV Infection and Oncogenesis

by Rachel Katzenellenbogen

Viruses 2017, 9(7), 180; https://doi.org/10.3390/v9070180 - 10 Jul 2017

Cited by 40 | Viewed by 6456

Abstract

Telomerase extends the repetitive DNA at the ends of linear chromosomes, and it is normally active in stem cells. When expressed in somatic diploid cells, it can lead to cellular immortalization. Human papillomaviruses (HPVs) are associated with and high-risk for cancer activate telomerase [...] Read more.

Telomerase extends the repetitive DNA at the ends of linear chromosomes, and it is normally active in stem cells. When expressed in somatic diploid cells, it can lead to cellular immortalization. Human papillomaviruses (HPVs) are associated with and high-risk for cancer activate telomerase through the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT). The expression of hTERT is affected by both high-risk HPVs, E6 and E7. Seminal studies over the last two decades have identified the transcriptional, epigenetic, and post-transcriptional roles high-risk E6 and E7 have in telomerase induction. This review will summarize these findings during infection and highlight the importance of telomerase activation as an oncogenic pathway in HPV-associated cancer development and progression. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessFeature PaperReview

Virus/Host Cell Crosstalk in Hypoxic HPV-Positive Cancer Cells

by Karin Hoppe-Seyler, Julia Mändl, Svenja Adrian, Bianca J. Kuhn and Felix Hoppe-Seyler

Viruses 2017, 9(7), 174; https://doi.org/10.3390/v9070174 - 5 Jul 2017

Cited by 10 | Viewed by 8090

Abstract

Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The expression of the viral E6/E7 oncogenes plays a key role for HPV-linked oncogenesis. It recently has been found that low oxygen concentrations (“hypoxia”), as present in sub-regions of HPV-positive cancers, [...] Read more.

Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The expression of the viral E6/E7 oncogenes plays a key role for HPV-linked oncogenesis. It recently has been found that low oxygen concentrations (“hypoxia”), as present in sub-regions of HPV-positive cancers, strongly affect the interplay between the HPV oncogenes and their transformed host cell. As a result, a state of dormancy is induced in hypoxic HPV-positive cancer cells, which is characterized by a shutdown of viral oncogene expression and a proliferative arrest that can be reversed by reoxygenation. In this review, these findings are put into the context of the current concepts of both HPV-linked carcinogenesis and of the effects of hypoxia on tumor biology. Moreover, we discuss the consequences for the phenotype of HPV-positive cancer cells as well as for their clinical behavior and response towards established and prospective therapeutic strategies. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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Open AccessReview

Deciphering the Multifactorial Susceptibility of Mucosal Junction Cells to HPV Infection and Related Carcinogenesis

by Michael Herfs, Thing R. Soong, Philippe Delvenne and Christopher P. Crum

Viruses 2017, 9(4), 85; https://doi.org/10.3390/v9040085 - 20 Apr 2017

Cited by 29 | Viewed by 8286

Abstract

Human papillomavirus (HPV)-induced neoplasms have long been considered to originate from viral infection of the basal cell layer of the squamous mucosa. However, this paradigm has been recently undermined by accumulating data supporting the critical role of a discrete population of squamo-columnar (SC) [...] Read more.

Human papillomavirus (HPV)-induced neoplasms have long been considered to originate from viral infection of the basal cell layer of the squamous mucosa. However, this paradigm has been recently undermined by accumulating data supporting the critical role of a discrete population of squamo-columnar (SC) junction cells in the pathogenesis of cervical (pre)cancers. The present review summarizes the current knowledge on junctional cells, discusses their high vulnerability to HPV infection, and stresses the potential clinical/translational value of the novel dualistic model of HPV-related carcinogenesis. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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14 pages, 685 KiB

Open AccessMeeting Report

The Intersection of HPV Epidemiology, Genomics and Mechanistic Studies of HPV-Mediated Carcinogenesis

by Lisa Mirabello, Megan A. Clarke, Chase W. Nelson, Michael Dean, Nicolas Wentzensen, Meredith Yeager, Michael Cullen, Joseph F. Boland, NCI HPV Workshop, Mark Schiffman and Robert D. Burk

Viruses 2018, 10(2), 80; https://doi.org/10.3390/v10020080 - 13 Feb 2018

Cited by 83 | Viewed by 13095

Abstract

Of the ~60 human papillomavirus (HPV) genotypes that infect the cervicovaginal epithelium, only 12–13 “high-risk” types are well-established as causing cervical cancer, with HPV16 accounting for over half of all cases worldwide. While HPV16 is the most important carcinogenic type, variants of HPV16 [...] Read more.

Of the ~60 human papillomavirus (HPV) genotypes that infect the cervicovaginal epithelium, only 12–13 “high-risk” types are well-established as causing cervical cancer, with HPV16 accounting for over half of all cases worldwide. While HPV16 is the most important carcinogenic type, variants of HPV16 can differ in their carcinogenicity by 10-fold or more in epidemiologic studies. Strong genotype-phenotype associations embedded in the small 8-kb HPV16 genome motivate molecular studies to understand the underlying molecular mechanisms. Understanding the mechanisms of HPV genomic findings is complicated by the linkage of HPV genome variants. A panel of experts in various disciplines gathered on 21 November 2016 to discuss the interdisciplinary science of HPV oncogenesis. Here, we summarize the discussion of the complexity of the viral–host interaction and highlight important next steps for selected applied basic laboratory studies guided by epidemiological genomic findings. Full article

(This article belongs to the Special Issue Expert Views on HPV Infection)

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