Papillomavirus Research: From Natural History To Vaccines and Beyond | Book
Caister Academic Press
M. Saveria Campo Division of Pathological Sciences, Institute of Comparative Medicine University of Glasgow, Glasgow G61 1QH, UK
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Papillomaviruses are oncogenic DNA tumour viruses that infect humans and animals. Human papillomavirus is one of the most common causes of sexually transmitted infection in the world and can also cause cancer. Papillomavirus research has been revolutionised in recent years with the advent of new technologies such as organotypic raft cultures, virus-like particles and transgenic mice. New facets of virion structure, life cycle, immunology and oncogenicity have recently emerged.
In this timely book leading scientists review current aspects of papillomavirus research providing a fascinating insight into papillomavirus molecular biology, interactions with the host, immunology and vaccine development. Topics covered include epidemiology and taxonomy, phylogenetic analyses, gene expression, regulation of DNA replication, transcription factor proteins, organotypic raft cultures, virus-like particles, and much more. Essential reading for scientists and researchers working on papillomavirus and a recommended text for anyone involved with antiviral drug and vaccine development.
"... provides a timely and comprehensive introduction to the field" from THE LANCET Infectious Diseases (2006) 6: 198.
"In its scope and detail 'Papillomavirus Research' has much to offer researchers working on papillomavirus or clinicians needing a comprehensive introduction to papillomavirus research." from THE LANCET Infectious Diseases (2006) 6: 198.
"... a very comprehensive overview of the state-of-the-art of PV research relating to taxonomy, molecular biology, natural history of the infection (in organotypic raft cultures and animal models), immunobiology, epidemiology and prevention by vaccination. Reviews are up-to-date." from Microbiology Today (2006)
"...the single most complete review of the PV field in one volume. As well as being a useful reference book within which to find specific information, it is also, in its complete form, a good read. It has already become a valuable resource in our laboratory." by Clare Davy (National Institute for Medical Research, Mill Hill, London) in Future Virology (2006) 1: 423-424
"This new book, edited by Professor M. Saveria Campo, constitutes a superb account of the varied and manifold research conducted on PVs" from J. Antimicrobial Chemother. (2006) 57: 1021
"... the chapters are very informative, and they provide in-depth discussions of the particular subject areas and comprehensive bibliographies ... a useful addition to the library" from Clin. Inf. Dis. (2006) 43: 1229-1230
"this is an excellent review of both human and animal papillomaviruses ... recommended for both papillomavirus researchers and those interested in this field." from ASM Microbe (November 2006)
M. Saveria Campo
- Large Format (210mm x 276mm)
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- Completely Up To Date
No Abstract is available. Therefore we present the first paragraph of this chapter. Papillomaviruses (PVs) are oncogenic DNA tumour viruses (IARC, 1995). They infect cutaneous and mucous epithelia in a variety of animals, including humans, through cuts or abrasions, and induce papillomas or warts, which generally regress without eliciting any serious clinical problems in the host, but can occasionally persist and progress to malignancy. There are upward of 300 distinct types of PVs, including probably 200 different types of human papillomavirus (HPV), and it is likely that more types will be found, particularly in animals.
Linking Human Papillomaviruses to Cervical Cancer: A Long and Winding Road
Epidemiologic studies suggesting an infectious etiology of cervical cancer have prompted scientist from different areas to search for the responsible agent. The human papillomaviruses (HPV) came into the play as members of a family of animal tumor viruses and because of their known association with genital infections. A long chain of events ranging from the identification of the plurality of HPVs, the regular finding of genomes of certain types, so called high-risk, within tumor biopsies, insights into the transforming mechanism and informative epidemiological surveys finally led to the consensus view within the scientific community of a causative link between these viruses and cervical cancer. This awareness triggered the development of HPV-specific vaccines as means of cancer prevention.
Phylogeny and Taxonomy of Papillomaviruses.
Papillomaviruses (PVs) have similar genomic organizations, and any pair of two PVs contains at least five homologous genes, although the nucleotide sequence may diverge by more than 50%. Phylogenetic algorithms that permit to compare homologies led to phylogenetic trees that have a similar topology independently of the gene analyzed. Phylogenetic studies strongly suggest that PVs normally evolve together with their mammalian and bird host species, do not change host species, do not recombine, and have maintained their basic genomic organization for a period exceeding 100 million years. These sequence comparisons have laid the foundation for a PV taxonomy, which is now officially recognized by the International Committee on Taxonomy of Viruses. All PVs form the family "Papillomaviridae
", which is distinct from the "Polyomaviridae
" thus eliminating the term "Papovaviridae
". Major branches of the phylogenetic tree of all PVs are considered as "genera", which are identified by Greek letters. Minor branches are considered "species" and unite PV types that are genomically distinct without exhibiting known biological differences. This new taxonomic system does not affect the traditional identification and characterization of PV "types" and their independent isolates with minor genomic differences, referred to as "subtypes" and "variants", all of which are taxa below the level of "species". Understanding the tremendous diversity of PV types, the worldwide distribution of variants of individual human PV (HPV) types, and their potential pathogenic distinctions, continue to be challenges for phylogenetic research and etiological considerations.
Epidemiology of Human Papillomavirus Infections and Associations with Cervical Cancer: New Opportunities For Prevention
F. Xavier Bosch, Silvia de Sanjosé, Xavier Castellsagué, Víctor Moreno, Nubia Muñoz
Historical studies on cervical cancer epidemiology repeatedly pointed out associations with sexual behavioral traits of women and men and with markers of sexually transmitted diseases. When the technology was developed and allowed testing for the DNA of the Human Papillomavirus (HPV) in exfoliated cervical cells epidemiological studies were able to confirm that most of the observed associations were in fact mediated by the persistent presence of HPV DNA. The finding is of utmost importance because a group of some 15 high-risk HPV types seem to be necessary for the development of all cervical cancer cases worldwide. As a consequence, the strategies for prevention are rapidly evolving towards the incorporation of HPV tests as a screening tool and the testing of novel HPV vaccines. Evidence to date indicates that HPV tests are at least as efficient as conventional cytology as primary screening test and superior to repeated cytology in the triage of the smears of uncertain significance. Phase II trials have shown that HPV vaccines are highly immunogenic and protect women from persistent type specific HPV infections. The paradigm of cervical cancer prevention is likely to change in the forthcoming years.
Gene Expression of Papillomaviruses.
Mina Kalantari and Hans-Ulrich Bernard
All papillomaviruses (PVs) contain a 400-850 bp long noncoding region (referred to as long control region, LCR, or upstream regulatory region, URR), which is positioned between the L1 and E6 genes and contains most of the elements that regulate transcription. All PVs have in common that transcription of early and late genes occurs uni-directionally from one or several promoters located in the LCR or in the E6 and E7 genes. All transcripts undergo differential splicing, which processes the seven to nine genes of PVs to numerous different polycistronic mRNAs. The detailed mechanisms that regulate transcription vary significantly between remotely related PVs such as animal PVs, cutaneous human PVs (HPVs), and alpha (or "genital") PVs. This review concentrates on the latter group, which has been most thoroughly studied. All alpha PVs contain an E6 promoter that is activated by a TATA box and an Sp1 binding site and down-regulated through a feedback loop executed by HPV E2 proteins. An enhancer, centered about 400 bp upstream of the E6 promoter, activates transcription specifically in epithelial cells by the synergism between numerous different transcription factors, with AP-1 playing a major role in the epithelial specificity. The specificity of this enhancer is probably the sole source of the epitheliotropism of HPVs. A silencer, modulated by YY1 and CDP, is positioned between the enhancer and the promoter, and appears to be important to couple HPV transcription with the differentiation of stratified epithelia. The HPV DNA exists in the nucleus of infected cells in the form of chromatin, i.e. wrapped around nucleosomes. The nucleosomal structure determines the accessibility of cis-responsive elements and is modulated by histone acetylation and deacetylation that is mediated by some of the factors that bind the enhancer and the silencer, and by DNA methylation. Yet other mechanisms influencing HPV gene expression include mRNA stability and altered transcription after recombination between HPV genomes and host DNA. The interactions between these different regulatory levels are likely a major source that determines the alternative outcomes of HPV infections, namely persistence in a subclinical state or progression to benign and malignant lesions.
Mechanisms and Regulation of Papillomavirus DNA Replication
Louise T. Chow and Thomas R. Broker
Human and animal papillomaviruses each contain a double-stranded circular DNA genome of approximately 7,400 to 8,200 base pairs which replicates as multicopy, extrachromosomal plasmids in the nucleus of infected keratinocytes. To initiate DNA synthesis from the origin of replication (ori), papillomaviruses encode an ori recognition protein E2 and a replicative DNA helicase E1. All other replication proteins as well as anabolic systems that synthesize the deoxynucleotide substrates are supplied by the host. In cycling cells, viral DNA replication maintains a steady copy number of viral genomes per cell. In post-mitotic, differentiated keratinocytes the papillomaviruses induce the host cells back into S-phase and viral DNA undergoes multiple rounds of replication for progeny virion production. In this Chapter, we summarize the findings of numerous laboratories on the mechanisms regulating the initiation of papillomaviral DNA replication as well as the maintenance and amplification of viral DNA, as characterized by in vitro
assays independent of other viral proteins that are required in the context of the whole genomic sequence in the host tissues.
The Papillomavirus Transcription/Replication Factor E2: Structure, Function, Cancer and Therapy
Iain M. Morgan and Mary M. Donaldson
As with all papillomavirus (PV) proteins, E2 has been studied in a number of systems with BPV1 providing the original paradigm. Extensive work has also been carried out investigating HPV 16, 18, 11, 6, and 31 E2 proteins amongst others. This chapter will begin with an introduction to the E2 protein and its general structure and function and will then go on to discuss more specific roles. The role of E2 and interacting partners in viral replication and transcription will be discussed, as well as their role in segregating viral genomes and regulating the host cell cycle. Finally, the status of E2 expression in cancer will be discussed and also strategies for therapeutically targeting the E2 protein for the treatment of PV related diseases.
The E4 Protein - A Late Starter
E4, expressed as a fusion protein (E1^E4), is the major protein expressed in papillomavirus (PV) infections. Its role in the PV life cycle is still unknown although emerging evidence suggests that it acts as a major regulator of the productive phase of the life cycle. However, an earlier role in the infectious cycle cannot be dismissed. E4 interacts with, and in some cases disrupts the organization of, a number of cytoplasmic and nuclear structures and organelles, including keratin intermediate filaments, the cornified cell envelope, mitochondria and ND10 domains. E4 can interfere with the normal progression of the cell cycle, and for some PV types this function seems to be regulated partly by posttranslational modification of the E4 protein. Few cellular partners of E4 have been identified, but one of these interactors is a cellular factor involved in mRNA metabolism. Thus, E4 is likely to have a pleiotropic role in the PV life cycle. To date, E4 functions suggest a role in facilitating and supporting viral genome amplification, the regulation of late gene expression, control of virus maturation and mediation of virus release.
Biological Activities of Papillomavirus E5 Proteins
Frank A. Suprynowicz, M. Saveria Campo and Richard Schlegel
This chapter discusses biological activities of the bovine papillomavirus type 1 E5 protein (BPV-1 E5), the closely-related E5 protein of bovine papillomavirus type 4 (BPV-4 E5) and the E5 protein of high-risk human papillomavirus type 16 (HPV-16 E5). BPV-1 E5 transforms fibroblasts by inducing constitutive, ligand-independent activation of the β-type platelet-derived growth factor receptor (PDGF-Rβ
), and by constitutively activating c-Src and interfering with Golgi acidification independently of PDGF-Rβ
signaling. BPV-4 E5 similarly transforms fibroblasts and disrupts gap junction-mediated intercellular communication. Both BPV proteins down-regulate surface expression of major histocompatibility complex (MHC) class I molecules, which should enhance the ability of infected cells to evade detection by the host immune system. HPV-16 E5 is only weakly oncogenic, but acts in a number of ways to increase the duration and scope of HPV-16 infections, which in turn may increase the probability of malignant progression. These actions include a reduction of MHC class I and class II surface expression, the disruption of gap junctional intercellular communication and the enhancement of ligand-dependent epidermal growth factor receptor activation.
The Role of the HPV E6 Oncoprotein in Malignant Progression.
Miranda Thomas, David Pim and Lawrence Banks.
It is now well established that the continued expression of the two major viral oncoproteins, E6 and E7, is essential for the maintenance of the transformed phenotype in cells derived from cervical tumours. Numerous in vitro
and in vivo
systems have been used to address the respective contributions of each protein to the development of malignancy. Recent studies have begun to highlight a role for E6 in the later, more malignant, stages of disease progression. Therefore, understanding the mechanisms by which E6 brings this about has important implications both for virus-induced cancers and for cancer progression in general. Interestingly, a recently identified class of cellular E6 targets has been implicated in this activity. These proteins control processes regulating cell proliferation, cell polarity, and cell-cell contact, all of which are perturbed during metastatic progression. In this chapter we shall review the activities of E6 with respect to those cellular targets that may be responsible for driving the later stages of malignant progression.
The Biology of the E7 protein of HPV-16
Dennis J. McCance
The E7 protein of oncogenic human papillomaviruses (HPV), such as HPV-16, is essential for the replication of the virus in the stratified epithelium. Replication of the viral genome requires that the terminally differentiating keratinocytes are induced back into the cell cycle to provide the necessary environment for DNA propagation. An unwanted outcome of this cell cycle stimulation is the immortalization of the infected cells, which along with unknown mutations in the genome of the infected cells, may lead to a malignant phenotype. In this Chapter, I will describe properties of E7 that are consistent with the ability of the protein to inhibit keratinocyte differentiation, stimulate cell cycle progression and cause immortalization of keratinocytes.
Organotypic Raft Cultures and the Study of the Natural History of Papillomavirus
Jason M. Bodily, Samina Alam, Horng-Shen Chen, and Craig Meyers
Organotypic (raft) cultures have proven to be a valuable tool for understanding the natural history of papillomaviruses (PVs). Through generation of fully differentiated and permissive epithelium in vitro
, insights have been gained into the response of PVs to differentiation throughout their normal life cycles, as well as how the viruses contribute to loss of differentiation and progression toward malignancy. In this chapter, we will focus entirely on studies of HPV biology that have used raft culture to arrive at important conclusions. We first review the history of raft culture and the use of rafts in the study of PVs and genital cancer. Studies of normal and altered differentiation, production of virions in vitro
, gene expression and function during the normal life cycle, interactions with the cell cycle machinery, and malignant progression will be discussed. We will also examine studies that use raft culture to understand the immunology of PVs, interaction with other virus types and cofactors, and therapeutic testing. Finally, we will discuss areas of papillomavirus biology that remain largely unexplored but that are accessible for study through the use of this important technology.
Early Events in the Papillomaviral Lifecycle
Patricia M. Day and John T. Schiller
The chapter follows the chronological transit of the PV virion from the initial interaction with the cell surface until delivery into the nucleus. The interaction of the particle with the cell surface occurs largely via interaction of the major capsid protein, L1, with cell surface heparan sulfate proteoglycans. It is unclear if a secondary receptor is involved. It is also unclear if the minor capsid protein, L2, plays a role in cell surface interactions. Most PV types that have been examined appear to enter the cell via a clathrin-dependent endocytic pathway. Infection can be abrogated by inhibitors of this pathway and colocalization of capsid proteins with markers of the early and late endosomal compartments has been observed. It has recently been proposed that L2 can mediate the escape of the virus from the endosome by lysis of the limiting membrane. L2 and the genome traffic into the nucleus and colocalize at ND10. Localization to this domain is critical for efficient transcription of the PV genome.
Late Events in the Life Cycle of Human Papillomaviruses
Sheila V. Graham
Late events in the life cycle of human papillomaviruses (HPVs) include vegetative viral DNA replication, capsid protein production, virion assembly and virus transmission. Such late events are tightly linked to differentiation of the epithelium that the virus infects. The molecular mechanisms underpinning these events are not completely understood as yet but clearly involve contributions from both the host cell and the virus genome itself. This chapter summarises the main late events in the infectious life cycle. Current knowledge of virus late gene expression and its regulation is detailed. In particular, the interplay between viral early and late promoters and the important role of negative regulatory elements that reside in viral late RNAs are discussed. Finally, the putative trafficking and assembly pathways involving host cell and viral gene products that result in production of infectious virus particles are outlined.
Transgenic Mouse Models for the In Vivo Analysis of Papillomavirus Oncogene Function
Paul F. Lambert, Scott J. Balsitis, Anny Shai, Sara J.S. Simonson, Sybil M.G. Williams
The E6 and E7 oncoproteins of the high risk HPVs are recognized multifunctional proteins that can affect multiple cellular processes implicated in tumorigenesis. in vivo
models are critical to appreciate fully the oncogenic properties of HPV genes in the context of the appropriate organ sites. As with other cancers, the preferred animal for studying human cancers in the laboratory is the mouse owing to the advent of genetic engineering, the wealth of prior knowledge gained in areas like chemical carcinogenesis, genetic modifiers of cancers, development and pathology, as well as their practical value given their small size, short gestational period and the availability of genetically inbred strains. This chapter reviews the knowledge gained from the study of HPV transgenic mouse models. HPV transgenic mouse models have provided the means for dissecting the role of viral genes in cancer, and biological systems in which to develop and test new modalities for treating HPV-associated disease. Their study has provided compelling proof in support of the original hypothesis that HPVs cause cancer.
HPV and Oesophageal Carcinoma
Oesophageal squamous cell carcinoma (SCC) has a peculiar geographic distribution, with up to 500-fold variations in incidence between the low- and high-risk regions. The first reports suggesting HPV involvement in both benign and malignant squamous cell tumours of the esophagus date back to 1982. The abundant literature accumulated on this subject is summarised in this review. To date, 322 Oesophageal squamous cell papillomas (SCP) have been analysed using different HPV detection methods in 32 separate studies. HPV has been detected in 26.1% (84) of these cases. Until now, 1,485 SCCs have been examined by in situ hybridisation, of which 22.9% (341/1.485) were HPV DNA positive. This is almost identical with the 22.3% prevalence rate calculated among 2,645 SCCs analysed by PCR (589/2,645). HPV prevalence bears a close correlate to the incidence of SCC, being low (0-3%) and high (up to 80%) in the respective geographic regions. In large-scale seroepidemiological studies, the increased risk for SCC among HPV16-seropositives has reached OR (odds ratios) up to 15, even in low-incidence countries. Screening studies in high-incidence areas of China using balloon cytology sampling report high prevalence of HPV DNA among asymptomatic subjects. There are close human parallels to both SCP and SCC in the cattle, linked with BPV4 and alimentary carcinogens, present in bracken fern. in vitro
experiments on HPV-positive cancer cell lines implicate similar molecular mechanisms to those involved in HPV-associated genital carcinogenesis. The current data suggest that the (multifactorial) aetiology of oesophageal cancer differs between the low- and high-incidence geographic areas. Oncogenic HPV types probably play an important causal role only in the high-incidence regions.
Recurrent Respiratory Papillomatosis, HPV, and Impact on Host Response
Andrea Vambutas and Bettie M. Steinberg
Recurrent Respiratory Papillomatosis (RRP) is a devastating disease characterized by multiple recurrent, benign growths that cause significant morbidity by airway obstruction. Adjunct therapy to traditional surgical removal has been sought due to the aggressive nature of the disease. The lesions are caused by human papillomavirus (HPV) type 6 and 11. Although many of the same papillomavirus proteins are expressed in high risk HPV types, the function of these proteins are different in the low risk HPVs 6 and 11. In laryngeal papillomas cells, there is a defect in terminal differentiation and significant alterations in signal transduction. Latent viral infection is commonplace, and the triggers for activation of latency are unknown. Host immune responses demonstrate local immunocompromise, where many components for an appropriate immune response are reduced in papillomas. Ubiquitously expressed viral proteins are obvious targets for vaccine development. Unfortunately, the two most common targets, E6 and E7, either fail to induce any response or initiate inappropriate Th2-like responses. This has led investigators to increase immunogenicity of these proteins. To date, a completely successful therapeutic vaccine has not been identified. An ideal therapeutic vaccine in RRP would require the control of active and latent disease, with a minimal inflammatory response.
The Cutaneous Human Papillomavirus Types and Non-melanoma Skin Cancer
Veronique Bouvard, Anne-Sophie Gabet, Rosita Accardi, Bakary S. Sylla and Massimo Tommasino
Non-melanoma skin cancer (NMSC) is the most common form of malignancy in Caucasian adult populations. UV light is a key environmental risk factor for NMSC. The fact that impairment of the immune system increases the risk for development of skin cancers strongly suggests that infectious agents are also involved in their aetiology. The epitheliotropic human papillomaviruses (HPVs) are likely candidates, especially those classified in the genus beta of the HPV phylogenetic tree, also known as Epidermodysplasia verruciformis
(EV) HPV types. Independent investigations have shown that the DNA of several EV HPV types is highly prevalent in NMSC of both immunocompromised and immunocompetent individuals. Despite this association, however, a direct role of the EV HPV types in the development of NMSC remains to be proven. Due to the lack of a universal protocol for detection of EV HPV types, many studies using various methods have found different spectra of HPV types in skin lesions. Thus, it is still not known whether, within the genus beta, certain HPV types are more prevalent than others in malignant skin lesions. In addition, EV HPVs appear to be highly ubiquitous, being commonly detected in healthy skin of both immunocompromised and immunocompetent individuals. Functional studies on mucosal high-risk HPV types have clearly demonstrated that the products of two early genes, E6 and E7, play a key role in the transformation of infected cells by disrupting the regulation of cell cycle and apoptosis. Very little is known about the biological properties of E6 and E7 of the majority of EV HPV types. Partial characterization of a limited number of skin HPV types (EV and non-EV) has revealed that also their E6 and E7 proteins have the ability to interfere with the regulation of apoptosis and cell cycle. These findings need confirmation in studies in which additional HPV types are included to establish the biological significance of these events. In conclusion, some cutaneous HPV types may be involved in skin cancer development. However, the initial functional data indicate that the molecular mechanisms leading to cellular transformation are different from those of mucosal HPV types. EV viruses may act only at early stages of carcinogenesis, by potentiating the deleterious effects of other carcinogens such as UV radiation. Further functional and epidemiological studies are required to evaluate this model.
Papillomavirus-like Particles and Their Applications in MolecularVirology, Human Serology and Vaccines
Richard B.S. Roden and Raphael P. Viscidi
The discovery early in the 1990s that the major capsid protein of papillomaviruses, L1, assembles into virus-like particles (VLPs) has propelled prophylactic vaccine development and led to significant advances in the study of the natural history and molecular virology of this DNA tumor virus. VLPs present the conformational epitopes required for generating high titer neutralizing antibodies but are devoid of the potentially oncogenic viral genome. Therefore, VLPs are attractive candidates for a vaccine to prevent genital HPV infection. Indeed ongoing clinical vaccine trials with L1 VLPs demonstrate the induction of protective immunity. HPV VLPs have also been exploited as an antigen in enzyme-linked immunosorbant assays (ELISAs) to detect anti-virion immune responses in human sera. HPV 16 VLP-based ELISAs were the first HPV serological assays to have sufficient sensitivity and specificity to make them widely applicable to studies of the natural history of HPV infection and to demonstrate its association with neoplastic disease. Finally, studies of the molecular virology and immunology of oncogenic type papillomaviruses have been hampered by the difficulties in obtaining biochemical quantities of native virions. VLPs have been a useful surrogate for study of capsid structure, immunology and function in infection. In this chapter we summarize the dramatic impact of VLP technology in advancing our understanding of papillomavirus biology and immunology and discuss some of its limitations.
Immunobiology of Papillomaviruses
Margaret A Stanley
HPV infection is ubiquitous. In the genital tract almost all sexually active indivuals are infected at some point but most clear their infections without overt clinical disease. Lesions in which productive viral infection is occurring (ano-genital warts and CIN1) are not associated with inflammation or histological evidence of immune activity and HPV evades immune recognition by evading innate immune defences and delaying the activation of adaptive immunity. Regression of ano-genital warts is accompanied histologically by a response characteristic of cell mediated immunity, animal models support this and provide evidence that the response is regulated by CD4 T cell-dependent mechanisms. The increased prevalence of HPV infections in individuals immunosuppressed either as a consequence of organ transplantation or HIV infection demonstrates the central importance of the CD4 T cell population in the control of established HPV infections. Although it seems clear that the CD4 T cell subset is critical for the induction and regulation of the host response to HPV the nature of the effector response remains unclear. There is increasing evidence that NK cells and antigen specific CTLs recognising E2 and E6 are important effectors but CTL responses and the target antigens are still poorly understood.
Immune Evasion in Genital Papillomavirus Infection and Cervical Cancer: Role of Cytokines and Chemokines
Sigrun Smola-Hess and Herbert Pfister
Epidemiological and molecular studies of the past 20 years have provided evidence that persistent infection with human papillomaviruses (HPVs) is the main aetiological factor for development of cervical cancer. Most genital papillomavirus infections are cleared within one year. Yet, infections persist in up to one percent of immunocompetent individuals and progress to cancer. Cancer development usually takes a long period of time, eventually requiring decades. The increased incidences of squamous intraepithelial lesions (SIL, variously named cervical intraepithelial neoplasia, CIN) and cervical cancer in immunocompromised individuals strongly support a central role of the immune system in controlling HPV infection and progression. This chapter focuses on cytokines and chemokines in genital papillomavirus infection and cervical cancer as major regulators of the immune response, and discusses their role in immune evasion.
Michelle Giles and Suzanne M. Garland
Vaccines against human papillomavirus (HPV) may be prophylactic, therapeutic or a combination. Currently, prophylactic multivalent virus like particle (VLP) vaccines comprising the major capsid protein L1 are in Phase III clinical trials with preliminary results from Phase II trials indicating safety, plus 100% efficacy from persistent infection, as well as from infectious complications such as cervical dysplasia. The success of prophylactic vaccines is underpinned by their induction of neutralizing antibodies to the viral capsid, although we await long-term follow-up, to evaluate their prevention of neoplasia. Numerous therapeutic vaccines targeting nonstructural early viral antigens and including approaches such as peptide, viral-vector, DNA and dendritic cell vaccines are under investigation. Therapeutic vaccines are very much in their infancy compared with prophylactic vaccines, as although many show immunogenicity, this does not generally translate into reliable clinical responses. A number of these vaccines have been studied in phase I/II trials in humans, namely in women with cervical intraepithelial neoplasia (CIN), vulval intraepithelial neoplasia (VIN) and advanced cervical cancer. Although it is likely that a prophylactic vaccine will be licensed in the very near future, there are still many challenges to implementation of an effective HPV vaccine program, not the least of which will be cost effectiveness in setting where there are preventative screening programmes. Furthermore such challenges will differ from developed to developing countries. Challenges include unanswered questions such as the best age group to target, whether both genders should be vaccinated, the duration of efficacy, how vaccination will alter current recommendations for conventional cervical screening, whether there will be HPV genotype replacement, or genotype resistance, whether any cross protection will exist between genotypes, to how many genotypes can be placed in one vaccine. Of primary importance is whether the vaccine will be accessible and affordable to women in developing countries, where there is the greatest burden of HPV related disease. In addition, for successful vaccine implementation and uptake, there will need to be education of physicians, the general public, as well as those at government levels. The success of such vaccine programs will probably take many years to realize. Nevertheless, the prospect of a vaccine, which protects against the most common viral sexually transmitted infection and thereby protects against the complications of HPV infection such as cervical cancer, is extremely exciting. With current practices, the world projected rates of the burden of invasive cancer being over one million cases per year by 2050, primary prevention by the introduction of a successful HPV prophylactic vaccine should be one of the most significant public health initiatives of this decade.
HPV Vaccines in Plants: An Appetising Solution to Control Infection and Associated Cancers
Rosella Franconi and Aldo Venuti
The cultivation of plants with specific properties has been the foundation of medicine for millennia. Modern biotechnology may one day extend their medicinal uses to include the delivery of vaccines. Because of their low production costs and facility of use, plant-derived vaccines provide an interesting perspective. The simple demands for solar light, water and minerals make plants an economic system for the production of heterologous proteins, supplying eukaryotic post-translational modifications (e.g. glycosylation, phosphorylation), eliminating the risks of contaminations with animal pathogens and allowing oral administration. Other advantages stem from the possibility to express the protein of interest in reservoir organs, of production on wide scale and to omit purification passages, particularly for oral administration. In this case, crushed seeds, endosperma, fruits could be used for direct administration (edible vaccine). The list of plant-derived antigens, potentially usable as vaccines, continues to lengthen and includes pathogenic viral and bacterial proteins. In this chapter recent advances in production of prophylactic and therapeutic plant vaccines against papillomaviruses are reported. Some aspects of the public debate on the genetically modified organism will be discussed too.
Bovine Papillomavirus: Old System, New Lessons?
M Saveria Campo
Bovine papillomavirus (BPV) is perhaps the most extensively studied animal papillomavirus. BPVs induce exophytic papillomas of cutaneous or mucosal epithelia in cattle. The papillomas are benign tumours and generally regress without eliciting any serious clinical problems in the host, but occasionally persist and provide the focus for malignant transformation to squamous cell carcinoma, particularly in the presence of environmental cofactors. This has been experimentally demonstrated for cancer of the urinary bladder and cancer of the upper alimentary canal in cattle feeding on bracken fern. Six BPV types (BPV-1-6) have been characterised associated with specific, lesions with different histopathological characteristics. Recently the biology of BPV-5 has been reassessed, and novel types have been found, the biological characterisation of which is awaited with great interest. BPV has been studied both as an infectious agent in its own right and as a model in which to investigate the interaction of papillomavirus with its natural host and with environmental cofactors. It has also provided a powerful model for vaccination against human papillomavirus (PV). It continues to provide information applicable to HPV: new functions recently discovered for BPV proteins have been confirmed for HPV proteins.
Bovine Papillomaviruses and Equine Sarcoids
Lubna Nasir and Stuart W.J. Reid
Equine sarcoids are locally aggressive, non regressing, fibroblastic skin tumours representing the most common dermatological neoplasm reported in equidae. It is widely accepted that the Bovine Papillomavirus (BPV) types 1/2 are associated with the pathogenesis of sarcoid disease. The majority of lesions contain detectable viral nucleic acids and express the BPV 1/2 major transforming protein, E5, but appear to be non-productive for infectious virions. Here we review the evidence supporting association of sarcoids with bovine papillomavirus (BPV) and the nature of the infecting viral genomes and consider the practical implications of BPV infection for diagnostic and therapeutic purposes.
Rabbit Viral Papillomas and Carcinomas: Model Diseases for Human Papillomavirus Infections and Associated Carcinogenesis
Françoise Breitburd, Mathieu Nonnenmacher, Jérôme Salmon and Gérard Orth
Rabbit papillomaviruses are models of the natural history of diseases caused by oncogenic and non-oncogenic human papillomaviruses (tissue specificity, latency, regression, persistence, malignant progression). The cottontail rabbit papillomavirus (CRPV) induces skin warts in rabbits that may regress or persist depending on the host. Persistent warts may progress to invasive carcinoma. The rabbit oral papillomavirus causes papillomas of the oral and genital mucous membranes that usually regress. The CRPVb subtype, with strikingly divergent regulatory region and E6 and E7 oncogenes, induces warts with distinct immunogenic properties, significant differences in the levels of viral DNA replication and in the risk for malignant progression, allowing analysis of host and viral genetics controlling wart evolution and restriction to virus production. CRPV genetics, molecular biology of CRPV-induced benign and malignant tumors, rabbit immune responses, together with preventive and therapeutic vaccine design, antivirals, and immunomodulators, contribute to human papillomaviruses studies. Linkage of wart evolution to class II genes of the major histocompatibility complex allows the selection of rabbits with more predictable issues of CRPV infection, and the elucidation of the role of CD4+ cells, up-regulation of DQ antigens and down-regulation of class I antigens in the control of wart evolution, depending on rabbit haplotype and virus strain. Rabbit papillomaviruses will contribute to investigations of the genetic susceptibility to skin papillomavirus infection and carcinogenesis.
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