Small DNA Tumour Viruses
"invaluable for its multiple perspectives and concise summary of a large body of research" (MedicalScienceBooks.com)
"a good reference and review" (Doodys)
"a very valuable reference" (Microbiol. Today)
Caister Academic Press
Department of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK
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Small DNA tumour viruses are a fascinating group of double-stranded DNA viruses, made up of the polyomavirus, the adenovirus and the papillomavirus families. These viruses continue to provide fundamental insights into mammalian cell transformation, cell cycle control and tumour formation. The causal link between papillomaviruses and some human cancers is well known and a role for polyomavirus in human cancer has recently been established. Adenoviruses do not cause cancer in humans but as well as providing excellent tools for the study of host cell processes these viruses have been exploited as delivery vehicles in gene therapy for diseases such as cystic fibrosis and cancer. A common feature of small DNA tumour viruses is their heavy reliance on the host for survival and replication. Understanding the virus-host relationship is critical to understanding the tumourigenic process and how these viruses subvert the host's immune system.
In this timely book leading scientists from around the world review current hot-topics in this area providing a fascinating overview of the molecular biology of these viruses and their interactions with the host. Topics covered include: HPV infections and the production of HPV virion stocks; viral oncoproteins and their functions; the replication and maintenance of viral genomes; virus induced alterations in cellular miRNAs; viral deregulation of DNA damage responses; the initiation of viral DNA replication; induction of genomic instability by viral oncoproteins; targeting of PML proteins and PML nuclear bodies by these viruses; adenoviruses and gene therapy.
Essential reading for scientists and researchers working on small DNA tumour viruses and their associated diseases and a recommended text for anyone involved with DNA replication, DNA damage responses and genome instability, virus-host interactions, viral tumourigenesis or antiviral drug development.
"Cancer biology researchers interested in the transforming viruses will find the information contained in Small DNA Tumour Viruses to be highly applicable in terms of its strong molecular biology coverage. Virologists focused on this group of viruses will find this book invaluable for its multiple perspectives and concise summary of a large body of research in this area." from MedicalScienceBooks.com
"This is a good review of how viruses can hijack a host cell and induce unrestrained cellular replication. It will serve as a good reference and review for scientists working in this field as well as those developing vaccines and therapies for tumor-promoting viruses." from Doodys
"... written by leading researchers ... high quality and up to date... I particularly enjoyed the chapter on adenoviruses ... All in all this is a very useful book ... it is a very valuable reference for those who are entering the field, as well as those already ensconced" from Microbiology Today (2012)
Table of contents
1. Human Papillomavirus Infection and its Association With Neoplasia: From Molecular Biology to Prevention and Treatment
Richard Oparka and C. Simon Herrington
The papillomaviruses are diverse, predominantly epitheliotropic, viruses that are ubiquitous throughout the world. Well over 100 different types are known to infect humans, affecting particularly the squamous epithelia of the anogenital region, the skin and the upper aerodigestive tract. The majority of infections remain subclinical and, in many cases, HPV infection results in benign lesions such as warts that regress with elimination of the infection. However, infection with some HPV types, for example HPV 16 and 18, can also lead to malignant transformation. This association with malignant transformation has led to the development of vaccines against HPV and, in some countries, implementation of a vaccination programme. This chapter highlights the natural history of HPV-associated disease as well as the effects of the virus at a molecular level, and addresses the future implications of our knowledge of HPV infection for both prevention and treatment of HPV-associated disease.
2. The Art and Science of Obtaining Virion Stocks for Experimental Human Papillomavirus Infections
Michelle A. Ozbun and Michael P. Kivitz
Some human papillomaviruses (HPVs) have been propagated in the laboratory for ≈20 years; currently, there are multiple means for obtaining infectious virion stocks for experimental infections. Processes dependent upon epithelial differentiation for achieving virion production include natural warts, rodent xenografts, and cultured organotypic epithelial tissues. However, these options are not amenable for every HPV genotype, and virion yields are variable and viral genotype-dependent. Differentiation-dependent laboratory approaches are limited to virus production from replication-competent viral genomes and typically only viral genomes capable of conferring a significant cellular growth advantage can be maintained long-term. Cutaneous HPV and animal PV lesions yield the highest virion levels and pure stocks can be obtained for many cutaneous PVs. Only crude, low-purity virion stocks have been reported for carcinogenic HPVs (e.g., types 16, 18, 31) typically via organotypic tissue propagation. Advances in virion production methods independent of epithelial differentiation permit the isolation of high-titer, high purity viral stocks from virtually any cloned PV genotype. Based on the self assembly of transiently expressed capsid proteins to package DNA molecules of ≈5- to 8-kb in size, this approach provides the ability to produce infectious particles encapsidating any viral or reporter genome regardless of its replicative ability. These particles share many structural and functional similarities with differentiation-induced virions; however, questions remain about the absolute physiological likeness among PV stocks derived by different means. Herein we discuss advantages and disadvantages among the varied means of virion production, detail known similarities, and make note of potential disparities that have yet to be tested.
3. The Regulation of Human Papillomavirus Gene Expression by the E2 Protein: Keeping a Finger in Every Pie
Sheila Graham and Kevin L. Gaston
The human papillomavirus (HPV) genome is around 8000 base pairs in length and it encodes only eight proteins, a limited number of protein isoforms and no known microRNAs. Despite this relative paucity of genes and gene products these viruses are highly successful. Over 120 HPV types have been identified and they are the causative agents of a wide range of endemic prevalent diseases such as genital warts and common warts as well as rarer but much more serious diseases such as cervical cancer and penile cancer. In order to complete its life cycle HPV must harness the activities of the host cells to transcribe, translate and replicate the viral genome while simultaneously evading a battery of host defences. To facilitate these processes virally encoded non-structural proteins interact with a plethora of host cell proteins and manipulate many host cell regulatory pathways. This review focuses on the regulation of viral gene expression and in particular the diverse roles played by the viral E2 protein and its multiple cellular and viral binding proteins. E2 appears to function as a "master regulator", controlling viral gene expression at many levels while also enabling viral DNA replication and ensuring equal viral genome segregation during cell division. This impressive feat of multitasking is achieved via a network of E2-interacting proteins that includes almost all of the other viral proteins and a wide range of cellular partners.
4. HPV E5: An Enigmatic Oncoprotein
Laura F. Wetherill, Rebecca Ross and Andrew Macdonald
Mucosal papillomaviruses contain a short open reading frame (ORF) at the 3' end of the early region, termed E5. The E5 protein is a hydrophobic, membrane-integrated protein that localises to the endoplasmic reticulum, Golgi apparatus, endosomes and the nuclear envelope. Structural similarity to the bovine papillomavirus (BPV-1) E5 protein prompted an examination of the transforming abilities of human papillomavirus (HPV) E5, which revealed E5 to be a third oncoprotein encoded by HPV. In comparison to E6 and E7, less is understood of the role E5 plays in host transformation and the HPV lifecycle. Although recent findings have increased our knowledge of E5, the field is controversial and there is much work to be accomplished before we fully understand the many functions of this protein. This chapter summarises our latest understanding of the HPV E5 protein and its interactions with host cells, demonstrating that this protein is indeed of critical importance for HPV and worthy of further investigation.
5. E6 Oncoproteins: Structure and Associations
Scott B. Vande Pol
Papillomavirus E6 oncoproteins are small zinc-binding proteins with a bewildering array of biological activities, including modulation of apoptosis, cellular transcription, host cell differentiation, growth factor dependence, DNA damage responses, and cell cycle progression. How can such a tiny protein do so much? This review examines insights from studies of oncogenic human papillomavirus E6 and bovine papillomavirus E6 to illuminate the mechanism by which E6 proteins interact with cellular binding partners. The origins of E6 and the history of its investigation are presented with the discovery of the major interaction partners that mediate E6 effects on DNA damage responses, cellular transcription, and modulation of keratinocyte differentiation.
6. Biochemical and Structure-function Analyses of the HPV E7 Oncoprotein
Leonardo G. Alonso, Lucía B. Chemes, María L. Cerutti, Karina I. Dantur, and Gonzalo de Prat-Gay
The human papillomavirus E7 oncoprotein is the main transforming agent of this important pathogen. Although its primary action is binding and targeting the retinoblastoma tumour suppressor protein, over two decades of research has shown a much more complex mode of action where multiple cellular partners and cellular events take place before ultimate progression to carcinogenesis. In this chapter we describe the HPV16 E7 protein in biochemical terms in an attempt to understand some of the various interactions in which this protein participates. We describe its multiple equilibria and conformational species in solution and show that these can explain some of its puzzling promiscuous binding activities and we review the few interactions that have been addressed by biochemical and mechanistic approaches to date. We finally discuss the cellular localization of E7 conformers, how they influence its antigenic capacity, and how they can be exploited in therapeutic applications.
7. Replication and Maintenance of Viral Genomes by Association with Host Chromatin
Koenraad Van Doorslaer, Vandana Sekhar, Jameela Khan, and Alison A. McBride
Papillomaviruses persistently infect dividing epithelial cells. This cellular environment presents papillomaviruses with the challenge of having to replicate and retain their genome in proliferating cells. Papillomaviruses have evolved to maintain their genome as an extra-chromosomal element. The viral E2 protein binds to the viral genome and tethers it to the host chromosomes. This chapter will review some of the recent work showing how different papillomaviruses have evolved variations on this theme. Where appropriate, parallels will be drawn with other persistent, double-stranded DNA viruses.
8. Alterations in Cellular miRNAs Induced by Human Papillomaviruses
Amy S. Gardiner, Abigail I. Wald and Saleem A. Khan
In recent years, microRNAs (miRNAs) have been found to play important roles in the regulation of gene expression in mammalian cells. MiRNAs regulate many processes, including cell cycle progression, cell differentiation and organogenesis. Human cells encode approximately 1,000 miRNAs, and their expression has been shown to be altered in a variety of human cancers. Human papillomaviruses (HPVs) are DNA tumour viruses that are associated with cancers, especially cancers of the cervix and oropharynx. Recently, several studies have shown altered expression of miRNAs in HPV-associated cervical and oral cancers. In this article, we discuss the role of HPVs and their oncogenes in altering cellular miRNA expression, possible targets of such miRNAs, and how miRNA changes may contribute to the pathogenesis of HPV-associated cancers.
9. Viral Deregulation of DNA Damage Responses
Sergei Boichuk and Ole Gjoerup
Incoming viral genomes, aberrant viral replication structures or individual viral proteins are potential triggers of DNA damage responses (DDRs). In an emerging theme, viruses interfere with, and frequently commandeer, DDR and repair signaling pathways to promote the viral life cycle. Here we review the diverse mechanisms that small DNA tumour viruses utilize to deregulate DDR pathways. Adenoviruses (Ad) encode gene products that specifically degrade the MRN (Mre11, Rad50, Nbs1) damage sensor or sequester it in nuclear tracks. This causes an inhibition of both ATM and ATR responses. Failure to inactivate MRN leads to attenuation of viral replication and concatemerization of the viral genome, thus preventing efficient packaging. Conversely, polyomaviruses, like SV40, as well as human papillomaviruses (HPVs) appear to exploit the DDR, since they use components of it to positively regulate their life cycle, while generally inhibiting downstream checkpoint responses. SV40, mouse polyomavirus and HPV activate ATM signaling and benefit from it. Complexities of the interplay between small DNA tumour viruses and the DDR are continuously evolving and illuminate both critical aspects of the viral life cycle as well as basic cellular mechanisms operating in a non-viral setting.
10. Structural "Snap-shots" of the Initiation of SV40 Replication
Gretchen Meinke and Peter A. Bullock
The initiation of DNA replication, which is one of the fundamental processes in eukaryotic cells, is not understood at the molecular level. Therefore, several laboratories are attempting to understand this process using the Simian Virus 40 replication system; a relatively simple and well-characterized model for studies of eukaryotic DNA replication. The replication initiator encoded by Simian Virus 40 is termed T-antigen. Molecular structures have been obtained for the three major domains of T-antigen. Moreover, several structures are now available of the central "origin binding domain" in complex with various DNA substrates. Collectively these structures have provided a series of "snap-shots" of the initiation process. They have also significantly improved our understanding of such diverse processes as site specific binding during origin recognition, melting of origin sequences, oligomerization of T-antigen (to form hexamers and double hexamers) and the molecular basis for helicase activity.
11. Human Papillomavirus DNA Replication: Insights into the Structure and Regulation of a Eukaryotic DNA Replisome
Claudia M. D'Abramo, Amélie Fradet-Turcotte and Jacques Archambault
Human papillomaviruses (HPV) replicate their double-stranded, circular DNA genome using two virally encoded proteins, E1 and E2, and several components of the host DNA replication machinery. Viral DNA replication is initiated by the recruitment of the E1 helicase to the viral origin of replication, through its interaction with E2, where it assembles into double hexamers and interacts with cellular factors to form an active replication complex. As such, replication of the HPV genome bears many similarities with that of the host DNA at the biochemical level, making these small DNA tumour viruses excellent models for the study of eukaryotic DNA replication. This chapter will provide a detailed view of HPV DNA replication with an emphasis on the different mechanisms utilized by these viruses to maintain and amplify their genome in undifferentiated and differentiated keratinocytes, respectively, and how these processes are regulated by phosphorylation of the E1 protein.
12. Induction of Genomic Instability by Human Papillomavirus Oncoproteins
Karl Münger and Stefan Duensing
The high-risk human papillomavirus (HPV)-encoded oncoproteins E6 and E7 have been instrumental to dissect crucial pathways of genomic instability and carcinogenic progression. This includes the notion that cell cycle deregulation and the development of numerical and structural chromosomal instability are intricately linked. The HPV E6 and E7 oncoproteins disrupt p53 and pRB signaling, respectively, and it has become evident that these events set the stage for numerous host cellular aberrations that can promote genomic instability and thus ultimately promote malignant progression. Many if not all of these host cellular aberrations can also be detected in non-virus-associated tumours, making HPV-associated carcinogenesis an attractive model system to analyze the molecular mechanisms and functional consequences of genomic instability in cancer in general.
13. Targeting of PML Proteins and PML Nuclear Bodies by DNA Tumour Viruses
Keith N. Leppard and Jordan Wright
Promyelocytic leukaemia (PML) protein is the principal and much studied component of subnuclear structures known as PML NBs. These structures and/or their components have been implicated in a very wide range of cellular processes, without the precise mechanism of their involvement being determined. One of the key areas of PML study has been the interactions that many viruses make with PML NBs during infection, leading to the suggestion that PML NBs play a role in antiviral responses. This chapter reviews what is known about the interactions between various DNA tumour viruses and other viruses with PML NBs, and places this information in the wider context of the functions ascribed to PML NBs in the uninfected cell to consider what is the underlying purpose of this class of virus:host interactions.
14. Adenoviruses and Gene Therapy: The Role of the Immune System
Laura White and G. Eric Blair
Adenovirus (Ad)-based vectors have been frequently used as gene therapy vectors due to their ability to infect a wide range of dividing and non-dividing cells, their efficient growth to high titres in complementing cell lines and ease of genome manipulation. However, the transition of Ad vectors from in vitro studies to clinical application has been limited by sub-optimal efficacy and robust inflammatory responses elicited upon administration. In recent years it has become clear that multiple innate and adaptive responses limit the efficacy and safety of Ad vectors. In this review, we focus on the current understanding of the immune response to Ads with a particular focus on the innate immune response, and how this information can be used to design safer and more efficacious vectors.
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(EAN: 9781904455998 9781912530380 Subjects: [microbiology] [virology] [medical microbiology] [molecular microbiology] [genomics] )