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Special Issue "Tumour Viruses"

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A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (31 March 2015)

Special Issue Editor

Guest Editor
Dr. Joanna Parish (Website)

Royal Society University Research Fellow, School of Cancer Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK
Phone: 0121 4158151
Interests: papillomavirus; transcription; virus-host interactions; viral persistence; mitosis

Special Issue Information

Dear Colleagues,

Current worldwide estimates suggest that 15-20% of all cancers are caused by viral infections. At present, there are eight viruses that have a strong association with cancer development namely, human papillomavirus, Epstein-Barr virus, Kaposi’s sarcoma-associated herpes virus, human T-cell lymphotrophic virus type I, Merkel cell polyomavirus, hepatitis B and C viruses and human immunodeficiency virus. Some of these viruses and associated cancers, such as human papillomavirus and cervical cancer, are well studied and the causal link between infection and cancer development is established. However, the involvement of these known oncogenic viruses in cancer development at other body sites is not well understood and further study of these viruses continues to highlight novel mechanisms of cellular transformation. Other cancer-associated viruses are only recently discovered, such as Merkel cell polyomavirus, and further work is required to formally prove their role in cancer development. In this Special Issue, we seek to explore novel mechanisms of cellular transformation by oncogenic viruses, the role of viral infection in cancer development in understudied body sites and the potential role of novel viral pathogens in cancer development.

Dr. Joanna Parish
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1500 CHF (Swiss Francs).


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Keywords

  • tumour virus
  • cancer
  • emerging
  • undiscovered cancers/viruses
  • novel mechanism
  • epidemiology
  • post-vaccine

Published Papers (20 papers)

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Research

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Open AccessArticle HPV16 E6 Controls the Gap Junction Protein Cx43 in Cervical Tumour Cells
Viruses 2015, 7(10), 5243-5256; doi:10.3390/v7102871
Received: 15 May 2015 / Revised: 24 September 2015 / Accepted: 30 September 2015 / Published: 5 October 2015
Cited by 1 | PDF Full-text (5684 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Human papillomavirus type 16 (HPV16) causes a range of cancers including cervical and head and neck cancers. HPV E6 oncoprotein binds the cell polarity regulator hDlg (human homologue of Drosophila Discs Large). Previously we showed in vitro, and now in vivo [...] Read more.
Human papillomavirus type 16 (HPV16) causes a range of cancers including cervical and head and neck cancers. HPV E6 oncoprotein binds the cell polarity regulator hDlg (human homologue of Drosophila Discs Large). Previously we showed in vitro, and now in vivo, that hDlg also binds Connexin 43 (Cx43), a major component of gap junctions that mediate intercellular transfer of small molecules. In HPV16-positive non-tumour cervical epithelial cells (W12G) Cx43 localised to the plasma membrane, while in W12T tumour cells derived from these, it relocated with hDlg into the cytoplasm. We now provide evidence that E6 regulates this cytoplasmic pool of Cx43. E6 siRNA depletion in W12T cells resulted in restoration of Cx43 and hDlg trafficking to the cell membrane. In C33a HPV-negative cervical tumour cells expressing HPV16 or 18 E6, Cx43 was located primarily in the cytoplasm, but mutation of the 18E6 C-terminal hDlg binding motif resulted in redistribution of Cx43 to the membrane. The data indicate for the first time that increased cytoplasmic E6 levels associated with malignant progression alter Cx43 trafficking and recycling to the membrane and the E6/hDlg interaction may be involved. This suggests a novel E6-associated mechanism for changes in Cx43 trafficking in cervical tumour cells. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessArticle The Subcellular Localisation of the Human Papillomavirus (HPV) 16 E7 Protein in Cervical Cancer Cells and Its Perturbation by RNA Aptamers
Viruses 2015, 7(7), 3443-3461; doi:10.3390/v7072780
Received: 9 April 2015 / Revised: 17 June 2015 / Accepted: 17 June 2015 / Published: 26 June 2015
PDF Full-text (1690 KB) | HTML Full-text | XML Full-text
Abstract
Human papillomavirus (HPV) is the most common viral infection of the reproductive tract, affecting both men and women. High-risk oncogenic types are responsible for almost 90% of anogenital and oropharyngeal cancers including cervical cancer. Some of the HPV “early” genes, particularly E6 [...] Read more.
Human papillomavirus (HPV) is the most common viral infection of the reproductive tract, affecting both men and women. High-risk oncogenic types are responsible for almost 90% of anogenital and oropharyngeal cancers including cervical cancer. Some of the HPV “early” genes, particularly E6 and E7, are known to act as oncogenes that promote tumour growth and malignant transformation. Most notably, HPV-16 E7 interacts with the tumour suppressor protein pRb, promoting its degradation, leading to cell cycle dysregulation in infected cells. We have previously shown that an RNA aptamer (termed A2) selectively binds to HPV16 E7 and is able to induce apoptosis in HPV16-transformed cervical carcinoma cell lines (SiHa) through reduction of E7 levels. In this study, we investigated the effects of the A2 aptamer on E7 localisation in order to define its effects on E7 activity. We demonstrate for the first time that E7 localised to the plasma membrane. In addition, we show that A2 enhanced E7 localisation in the ER and that the A2-mediated reduction of E7 was not associated with proteasomal degradation. These data suggest that A2 perturbs normal E7 trafficking through promoting E7 ER retention. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessArticle Activation of DNA Damage Response Pathways during Lytic Replication of KSHV
Viruses 2015, 7(6), 2908-2927; doi:10.3390/v7062752
Received: 17 April 2015 / Revised: 29 May 2015 / Accepted: 29 May 2015 / Published: 5 June 2015
Cited by 4 | PDF Full-text (2448 KB) | HTML Full-text | XML Full-text
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is [...] Read more.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lytic reactivation of KSHV leads to activation of the ATM and DNA-PK DDR kinases resulting in phosphorylation of multiple downstream substrates. Inhibition of ATM results in the reduction of overall levels of viral replication while inhibition of DNA-PK increases activation of ATM and leads to earlier viral release. There is no activation of the ATR-CHK1 pathway following lytic replication and CHK1 phosphorylation is inhibited at later times during the lytic cycle. Despite evidence of double-strand breaks and phosphorylation of H2AX, 53BP1 foci are not consistently observed in cells containing lytic virus although RPA32 and MRE11 localise to sites of viral DNA synthesis. Activation of the DDR following KSHV lytic reactivation does not result in a G1 cell cycle block and cells are able to proceed to S-phase during the lytic cycle. KSHV appears then to selectively activate DDR pathways, modulate cell cycle progression and recruit DDR proteins to sites of viral replication during the lytic cycle. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessArticle Impact of Adenovirus E4-ORF3 Oligomerization and Protein Localization on Cellular Gene Expression
Viruses 2015, 7(5), 2428-2449; doi:10.3390/v7052428
Received: 31 March 2015 / Revised: 23 April 2015 / Accepted: 11 May 2015 / Published: 13 May 2015
Cited by 4 | PDF Full-text (1521 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Adenovirus E4-ORF3 protein facilitates virus replication through the relocalization of cellular proteins into nuclear inclusions termed tracks. This sequestration event disrupts antiviral properties associated with target proteins. Relocalization of Mre11-Rad50-Nbs1 proteins prevents the DNA damage response from inhibiting Ad replication. Relocalization [...] Read more.
The Adenovirus E4-ORF3 protein facilitates virus replication through the relocalization of cellular proteins into nuclear inclusions termed tracks. This sequestration event disrupts antiviral properties associated with target proteins. Relocalization of Mre11-Rad50-Nbs1 proteins prevents the DNA damage response from inhibiting Ad replication. Relocalization of PML and Daxx impedes the interferon-mediated antiviral response. Several E4-ORF3 targets regulate gene expression, linking E4-ORF3 to transcriptional control. Furthermore, E4-ORF3 was shown to promote the formation of heterochromatin, down-regulating p53-dependent gene expression. Here, we characterize how E4-ORF3 alters cellular gene expression. Using an inducible, E4-ORF3-expressing cell line, we performed microarray experiments to highlight cellular gene expression changes influenced by E4-ORF3 expression, identifying over four hundred target genes. Enrichment analysis of these genes suggests that E4-ORF3 influences factors involved in signal transduction and cellular defense, among others. The expression of mutant E4-ORF3 proteins revealed that nuclear track formation is necessary to induce these expression changes. Through the generation of knockdown cells, we demonstrate that the observed expression changes may be independent of Daxx and TRIM33 suggesting that an additional factor(s) may be responsible. The ability of E4-ORF3 to manipulate cellular gene expression through the sequestration of cellular proteins implicates a novel role for E4-ORF3 in transcriptional regulation. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available

Review

Jump to: Research, Other

Open AccessReview Recent Progress in Therapeutic Treatments and Screening Strategies for the Prevention and Treatment of HPV-Associated Head and Neck Cancer
Viruses 2015, 7(9), 5040-5065; doi:10.3390/v7092860
Received: 17 June 2015 / Revised: 17 August 2015 / Accepted: 27 August 2015 / Published: 17 September 2015
Cited by 3 | PDF Full-text (715 KB) | HTML Full-text | XML Full-text
Abstract
The rise in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has elicited significant interest in the role of high-risk HPV in tumorigenesis. Because patients with HPV-positive HNSCC have better prognoses than do their HPV-negative counterparts, current therapeutic strategies for [...] Read more.
The rise in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has elicited significant interest in the role of high-risk HPV in tumorigenesis. Because patients with HPV-positive HNSCC have better prognoses than do their HPV-negative counterparts, current therapeutic strategies for HPV+ HNSCC are increasingly considered to be overly aggressive, highlighting a need for customized treatment guidelines for this cohort. Additional issues include the unmet need for a reliable screening strategy for HNSCC, as well as the ongoing assessment of the efficacy of prophylactic vaccines for the prevention of HPV infections in the head and neck regions. This review also outlines a number of emerging prospects for therapeutic vaccines, as well as for targeted, molecular-based therapies for HPV-associated head and neck cancers. Overall, the future for developing novel and effective therapeutic agents for HPV-associated head and neck tumors is promising; continued progress is critical in order to meet the challenges posed by the growing epidemic. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Regulation of the Wnt/β-Catenin Signaling Pathway by Human Papillomavirus E6 and E7 Oncoproteins
Viruses 2015, 7(8), 4734-4755; doi:10.3390/v7082842
Received: 8 May 2015 / Revised: 6 August 2015 / Accepted: 17 August 2015 / Published: 19 August 2015
Cited by 4 | PDF Full-text (643 KB) | HTML Full-text | XML Full-text
Abstract
Cell signaling pathways are the mechanisms by which cells transduce external stimuli, which control the transcription of genes, to regulate diverse biological effects. In cancer, distinct signaling pathways, such as the Wnt/β-catenin pathway, have been implicated in the deregulation of critical molecular [...] Read more.
Cell signaling pathways are the mechanisms by which cells transduce external stimuli, which control the transcription of genes, to regulate diverse biological effects. In cancer, distinct signaling pathways, such as the Wnt/β-catenin pathway, have been implicated in the deregulation of critical molecular processes that affect cell proliferation and differentiation. For example, changes in β-catenin localization have been identified in Human Papillomavirus (HPV)-related cancers as the lesion progresses. Specifically, β-catenin relocates from the membrane/cytoplasm to the nucleus, suggesting that this transcription regulator participates in cervical carcinogenesis. The E6 and E7 oncoproteins are responsible for the transforming activity of HPV, and some studies have implicated these viral oncoproteins in the regulation of the Wnt/β-catenin pathway. Nevertheless, new interactions of HPV oncoproteins with cellular proteins are emerging, and the study of the biological effects of such interactions will help to understand HPV-related carcinogenesis. Viruses 2015, 7 4735 This review addresses the accumulated evidence of the involvement of the HPV E6 and E7 oncoproteins in the activation of the Wnt/β-catenin pathway. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Papillomavirus Infectious Pathways: A Comparison of Systems
Viruses 2015, 7(8), 4303-4325; doi:10.3390/v7082823
Received: 6 June 2015 / Revised: 6 June 2015 / Accepted: 23 July 2015 / Published: 4 August 2015
Cited by 2 | PDF Full-text (826 KB) | HTML Full-text | XML Full-text
Abstract
The HPV viral lifecycle is tightly linked to the host cell differentiation, causing difficulty in growing virions in culture. A system that bypasses the need for differentiating epithelium has allowed for generation of recombinant particles, such as virus-like particles (VLPs), pseudovirions (PsV), [...] Read more.
The HPV viral lifecycle is tightly linked to the host cell differentiation, causing difficulty in growing virions in culture. A system that bypasses the need for differentiating epithelium has allowed for generation of recombinant particles, such as virus-like particles (VLPs), pseudovirions (PsV), and quasivirions (QV). Much of the research looking at the HPV life cycle, infectivity, and structure has been generated utilizing recombinant particles. While recombinant particles have proven to be invaluable, allowing for a rapid progression of the HPV field, there are some significant differences between recombinant particles and native virions and very few comparative studies using native virions to confirm results are done. This review serves to address the conflicting data in the HPV field regarding native virions and recombinant particles. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia
Viruses 2015, 7(7), 3863-3890; doi:10.3390/v7072802
Received: 11 May 2015 / Revised: 3 July 2015 / Accepted: 7 July 2015 / Published: 16 July 2015
Cited by 13 | PDF Full-text (1637 KB) | HTML Full-text | XML Full-text
Abstract
Papillomaviruses have evolved over many millions of years to propagate themselves at specific epithelial niches in a range of different host species. This has led to the great diversity of papillomaviruses that now exist, and to the appearance of distinct strategies for [...] Read more.
Papillomaviruses have evolved over many millions of years to propagate themselves at specific epithelial niches in a range of different host species. This has led to the great diversity of papillomaviruses that now exist, and to the appearance of distinct strategies for epithelial persistence. Many papillomaviruses minimise the risk of immune clearance by causing chronic asymptomatic infections, accompanied by long-term virion-production with only limited viral gene expression. Such lesions are typical of those caused by Beta HPV types in the general population, with viral activity being suppressed by host immunity. A second strategy requires the evolution of sophisticated immune evasion mechanisms, and allows some HPV types to cause prominent and persistent papillomas, even in immune competent individuals. Some Alphapapillomavirus types have evolved this strategy, including those that cause genital warts in young adults or common warts in children. These strategies reflect broad differences in virus protein function as well as differences in patterns of viral gene expression, with genotype-specific associations underlying the recent introduction of DNA testing, and also the introduction of vaccines to protect against cervical cancer. Interestingly, it appears that cellular environment and the site of infection affect viral pathogenicity by modulating viral gene expression. With the high-risk HPV gene products, changes in E6 and E7 expression are thought to account for the development of neoplasias at the endocervix, the anal and cervical transformation zones, and the tonsilar crypts and other oropharyngeal sites. A detailed analysis of site-specific patterns of gene expression and gene function is now prompted. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Targeting CTCF to Control Virus Gene Expression: A Common Theme amongst Diverse DNA Viruses
Viruses 2015, 7(7), 3574-3585; doi:10.3390/v7072791
Received: 22 May 2015 / Revised: 30 June 2015 / Accepted: 2 July 2015 / Published: 6 July 2015
Cited by 1 | PDF Full-text (115 KB) | HTML Full-text | XML Full-text
Abstract
All viruses target host cell factors for successful life cycle completion. Transcriptional control of DNA viruses by host cell factors is important in the temporal and spatial regulation of virus gene expression. Many of these factors are recruited to enhance virus gene [...] Read more.
All viruses target host cell factors for successful life cycle completion. Transcriptional control of DNA viruses by host cell factors is important in the temporal and spatial regulation of virus gene expression. Many of these factors are recruited to enhance virus gene expression and thereby increase virus production, but host cell factors can also restrict virus gene expression and productivity of infection. CCCTC binding factor (CTCF) is a host cell DNA binding protein important for the regulation of genomic chromatin boundaries, transcriptional control and enhancer element usage. CTCF also functions in RNA polymerase II regulation and in doing so can influence co-transcriptional splicing events. Several DNA viruses, including Kaposi’s sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV) and human papillomavirus (HPV) utilize CTCF to control virus gene expression and many studies have highlighted a role for CTCF in the persistence of these diverse oncogenic viruses. CTCF can both enhance and repress virus gene expression and in some cases CTCF increases the complexity of alternatively spliced transcripts. This review article will discuss the function of CTCF in the life cycle of DNA viruses in the context of known host cell CTCF functions. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview The Human Papillomavirus E6 PDZ Binding Motif: From Life Cycle to Malignancy
Viruses 2015, 7(7), 3530-3551; doi:10.3390/v7072785
Received: 6 May 2015 / Revised: 24 June 2015 / Accepted: 25 June 2015 / Published: 2 July 2015
Cited by 5 | PDF Full-text (906 KB) | HTML Full-text | XML Full-text
Abstract
Cancer-causing HPV E6 oncoproteins are characterized by the presence of a PDZ binding motif (PBM) at their extreme carboxy terminus. It was long thought that this region of E6 had a sole function to confer interaction with a defined set of cellular [...] Read more.
Cancer-causing HPV E6 oncoproteins are characterized by the presence of a PDZ binding motif (PBM) at their extreme carboxy terminus. It was long thought that this region of E6 had a sole function to confer interaction with a defined set of cellular substrates. However, more recent studies have shown that the E6 PBM has a complex pattern of regulation, whereby phosphorylation within the PBM can regulate interaction with two classes of cellular proteins: those containing PDZ domains and the members of the 14-3-3 family of proteins. In this review, we explore the roles that the PBM and its ligands play in the virus life cycle, and subsequently how these can inadvertently contribute towards the development of malignancy. We also explore how subtle alterations in cellular signal transduction pathways might result in aberrant E6 phosphorylation, which in turn might contribute towards disease progression. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Modulation of DNA Damage and Repair Pathways by Human Tumour Viruses
Viruses 2015, 7(5), 2542-2591; doi:10.3390/v7052542
Received: 30 March 2015 / Accepted: 12 May 2015 / Published: 22 May 2015
Cited by 6 | PDF Full-text (2343 KB) | HTML Full-text | XML Full-text | Correction
Abstract
With between 10% and 15% of human cancers attributable to viral infection, there is great interest, from both a scientific and clinical viewpoint, as to how these pathogens modulate host cell functions. Seven human tumour viruses have been identified as being involved [...] Read more.
With between 10% and 15% of human cancers attributable to viral infection, there is great interest, from both a scientific and clinical viewpoint, as to how these pathogens modulate host cell functions. Seven human tumour viruses have been identified as being involved in the development of specific malignancies. It has long been known that the introduction of chromosomal aberrations is a common feature of viral infections. Intensive research over the past two decades has subsequently revealed that viruses specifically interact with cellular mechanisms responsible for the recognition and repair of DNA lesions, collectively known as the DNA damage response (DDR). These interactions can involve activation and deactivation of individual DDR pathways as well as the recruitment of specific proteins to sites of viral replication. Since the DDR has evolved to protect the genome from the accumulation of deleterious mutations, deregulation is inevitably associated with an increased risk of tumour formation. This review summarises the current literature regarding the complex relationship between known human tumour viruses and the DDR and aims to shed light on how these interactions can contribute to genomic instability and ultimately the development of human cancers. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Interaction of Human Tumor Viruses with Host Cell Surface Receptors and Cell Entry
Viruses 2015, 7(5), 2592-2617; doi:10.3390/v7052592
Received: 23 March 2015 / Accepted: 12 May 2015 / Published: 22 May 2015
Cited by 5 | PDF Full-text (597 KB) | HTML Full-text | XML Full-text
Abstract
Currently, seven viruses, namely Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV), high-risk human papillomaviruses (HPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human T cell lymphotropic virus type 1 (HTLV-1), have been described to be [...] Read more.
Currently, seven viruses, namely Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV), high-risk human papillomaviruses (HPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human T cell lymphotropic virus type 1 (HTLV-1), have been described to be consistently associated with different types of human cancer. These oncogenic viruses belong to distinct viral families, display diverse cell tropism and cause different malignancies. A key to their pathogenicity is attachment to the host cell and entry in order to replicate and complete their life cycle. Interaction with the host cell during viral entry is characterized by a sequence of events, involving viral envelope and/or capsid molecules as well as cellular entry factors that are critical in target cell recognition, thereby determining cell tropism. Most oncogenic viruses initially attach to cell surface heparan sulfate proteoglycans, followed by conformational change and transfer of the viral particle to secondary high-affinity cell- and virus-specific receptors. This review summarizes the current knowledge of the host cell surface factors and molecular mechanisms underlying oncogenic virus binding and uptake by their cognate host cell(s) with the aim to provide a concise overview of potential target molecules for prevention and/or treatment of oncogenic virus infection. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling
Viruses 2015, 7(5), 2485-2506; doi:10.3390/v7052485
Received: 19 March 2015 / Accepted: 8 May 2015 / Published: 21 May 2015
Cited by 7 | PDF Full-text (651 KB) | HTML Full-text | XML Full-text
Abstract
Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses [...] Read more.
Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellular proteins to interfere with signaling of innate and adaptive immune pathways. This results in impairment of interferon and pro-inflammatory cytokine production and subsequent immune cell attraction, as well as resistance to incoming signals from the immune system. Furthermore, hrHPV avoids the killing of infected cells by interfering with antigen presentation to antigen-specific cytotoxic T lymphocytes. Thus, hrHPV has evolved multiple mechanisms to avoid detection and clearance by both the innate and adaptive immune system, the molecular mechanisms of which will be dealt with in detail in this review. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview The Role of the DNA Damage Response throughout the Papillomavirus Life Cycle
Viruses 2015, 7(5), 2450-2469; doi:10.3390/v7052450
Received: 27 March 2015 / Accepted: 13 May 2015 / Published: 21 May 2015
Cited by 5 | PDF Full-text (586 KB) | HTML Full-text | XML Full-text
Abstract
The DNA damage response (DDR) maintains genomic integrity through an elaborate network of signaling pathways that sense DNA damage and recruit effector factors to repair damaged DNA. DDR signaling pathways are usurped and manipulated by the replication programs of many viruses. Here, [...] Read more.
The DNA damage response (DDR) maintains genomic integrity through an elaborate network of signaling pathways that sense DNA damage and recruit effector factors to repair damaged DNA. DDR signaling pathways are usurped and manipulated by the replication programs of many viruses. Here, we review the papillomavirus (PV) life cycle, highlighting current knowledge of how PVs recruit and engage the DDR to facilitate productive infection. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Mechanisms of Cancer Cell Killing by the Adenovirus E4orf4 Protein
Viruses 2015, 7(5), 2334-2357; doi:10.3390/v7052334
Received: 29 March 2015 / Revised: 23 April 2015 / Accepted: 30 April 2015 / Published: 7 May 2015
Cited by 2 | PDF Full-text (1238 KB) | HTML Full-text | XML Full-text
Abstract
During adenovirus (Ad) replication the Ad E4orf4 protein regulates progression from the early to the late phase of infection. However, when E4orf4 is expressed alone outside the context of the virus it induces a non-canonical mode of programmed cell death, which feeds [...] Read more.
During adenovirus (Ad) replication the Ad E4orf4 protein regulates progression from the early to the late phase of infection. However, when E4orf4 is expressed alone outside the context of the virus it induces a non-canonical mode of programmed cell death, which feeds into known cell death pathways such as apoptosis or necrosis, depending on the cell line tested. E4orf4-induced cell death has many interesting and unique features including a higher susceptibility of cancer cells to E4orf4-induced cell killing compared with normal cells, caspase-independence, a high degree of evolutionary conservation of the signaling pathways, a link to perturbations of the cell cycle, and involvement of two distinct cell death programs, in the nucleus and in the cytoplasm. Several E4orf4-interacting proteins including its major partners, protein phosphatase 2A (PP2A) and Src family kinases, contribute to induction of cell death. The various features of E4orf4-induced cell killing as well as studies to decipher the underlying mechanisms are described here. Many explanations for the cancer specificity of E4orf4-induced cell death have been proposed, but a full understanding of the reasons for the different susceptibility of cancer and normal cells to killing by E4orf4 will require a more detailed analysis of the complex E4orf4 signaling network. An improved understanding of the mechanisms involved in this unique mode of programmed cell death may aid in design of novel E4orf4-based cancer therapeutics. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview The Role of Merkel Cell Polyomavirus and Other Human Polyomaviruses in Emerging Hallmarks of Cancer
Viruses 2015, 7(4), 1871-1901; doi:10.3390/v7041871
Received: 13 March 2015 / Revised: 1 April 2015 / Accepted: 7 April 2015 / Published: 10 April 2015
Cited by 12 | PDF Full-text (925 KB) | HTML Full-text | XML Full-text
Abstract
Polyomaviruses are non-enveloped, dsDNA viruses that are common in mammals, including humans. All polyomaviruses encode the large T-antigen and small t-antigen proteins that share conserved functional domains, comprising binding motifs for the tumor suppressors pRb and p53, and for protein phosphatase 2A, [...] Read more.
Polyomaviruses are non-enveloped, dsDNA viruses that are common in mammals, including humans. All polyomaviruses encode the large T-antigen and small t-antigen proteins that share conserved functional domains, comprising binding motifs for the tumor suppressors pRb and p53, and for protein phosphatase 2A, respectively. At present, 13 different human polyomaviruses are known, and for some of them their large T-antigen and small t-antigen have been shown to possess oncogenic properties in cell culture and animal models, while similar functions are assumed for the large T- and small t-antigen of other human polyomaviruses. However, so far the Merkel cell polyomavirus seems to be the only human polyomavirus associated with cancer. The large T- and small t-antigen exert their tumorigenic effects through classical hallmarks of cancer: inhibiting tumor suppressors, activating tumor promoters, preventing apoptosis, inducing angiogenesis and stimulating metastasis. This review elaborates on the putative roles of human polyomaviruses in some of the emerging hallmarks of cancer. The reciprocal interactions between human polyomaviruses and the immune system response are discussed, a plausible role of polyomavirus-encoded and polyomavirus-induced microRNA in cancer is described, and the effect of polyomaviruses on energy homeostasis and exosomes is explored. Therapeutic strategies against these emerging hallmarks of cancer are also suggested. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Human Papillomavirus and Tonsillar and Base of Tongue Cancer
Viruses 2015, 7(3), 1332-1343; doi:10.3390/v7031332
Received: 13 February 2015 / Revised: 13 March 2015 / Accepted: 17 March 2015 / Published: 20 March 2015
Cited by 4 | PDF Full-text (628 KB) | HTML Full-text | XML Full-text
Abstract
In 2007, human papillomavirus (HPV) type 16 was recognized as a risk factor by the International Agency for Research on Cancer, for oropharyngeal squamous cell carcinoma (OSCC), where tonsillar and base of tongue cancer (TSCC and BOTSCC) dominate. Furthermore, patients with HPV-positive [...] Read more.
In 2007, human papillomavirus (HPV) type 16 was recognized as a risk factor by the International Agency for Research on Cancer, for oropharyngeal squamous cell carcinoma (OSCC), where tonsillar and base of tongue cancer (TSCC and BOTSCC) dominate. Furthermore, patients with HPV-positive TSCC and BOTSCC, had a much better clinical outcome than those with corresponding HPV-negative cancer and other head and neck cancer. More specifically, survival was around 80% for HPV-positive TSCC and BOTSCC vs. 40% five-year disease free survival, for the corresponding HPV-negative tumors with conventional radiotherapy and surgery, while this could not be observed for HPV-positive OSCC at other sites. In addition, the past 20–40 years in many Western Countries, the incidence of HPV-positive TSCC and BOTSCC has risen, and >70% are men. This has resulted in a relative increase of patients with HPV-positive TSCC and BOTSCC that may not need the intensified chemo-radiotherapy (with many more severe debilitating side effects) often given today to patients with head and neck cancer. However, before tapering therapy, one needs to enable selection of patients for such treatment, by identifying clinical and molecular markers that together with HPV-positive status will better predict patient prognosis and response to therapy. To conclude, there is a new increasing group of patients with HPV-positive TSCC and BOTSCC with good clinical outcome, where options for better-tailored therapy are needed. For prevention, it would be of benefit to vaccinate both girls and boys against HPV16 infection. For potential future screening the ways to do so need optimizing. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Role of Host MicroRNAs in Kaposi’s Sarcoma-Associated Herpesvirus Pathogenesis
Viruses 2014, 6(11), 4571-4580; doi:10.3390/v6114571
Received: 26 October 2014 / Revised: 14 November 2014 / Accepted: 14 November 2014 / Published: 21 November 2014
Cited by 4 | PDF Full-text (384 KB) | HTML Full-text | XML Full-text
Abstract
MicroRNAs (miRNAs) are small non-coding RNA species that can bind to both untranslated and coding regions of target mRNAs, causing their degradation or post-transcriptional modification. Currently, over 2500 miRNAs have been identified in the human genome. Burgeoning evidence suggests that dysregulation of [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNA species that can bind to both untranslated and coding regions of target mRNAs, causing their degradation or post-transcriptional modification. Currently, over 2500 miRNAs have been identified in the human genome. Burgeoning evidence suggests that dysregulation of human miRNAs can play a role in the pathogenesis of a variety of diseases, including cancer. In contrast, only a small subset of human miRNAs has been functionally validated in the pathogenesis of oncogenic viruses, in particular, Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV is the etiologic agent of several human cancers, such as primary effusion lymphoma (PEL) and Kaposi’s sarcoma (KS), which are mostly seen in acquired immune deficiency syndrome (AIDS) patients or other immuno-suppressed subpopulation. This review summarizes recent literature outlining mechanisms for KSHV/viral proteins regulation of cellular miRNAs contributing to viral pathogenesis, as well as recent findings about the unique signature of miRNAs induced by KSHV infection or KSHV-related malignancies. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available
Open AccessReview Human Viruses and Cancer
Viruses 2014, 6(10), 4047-4079; doi:10.3390/v6104047
Received: 1 August 2014 / Revised: 18 September 2014 / Accepted: 13 October 2014 / Published: 23 October 2014
Cited by 13 | PDF Full-text (1412 KB) | HTML Full-text | XML Full-text
Abstract
The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- [...] Read more.
The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- have been consistently linked to different types of human cancer, and infections are estimated to account for up to 20% of all cancer cases worldwide. Viral oncogenic mechanisms generally include: generation of genomic instability, increase in the rate of cell proliferation, resistance to apoptosis, alterations in DNA repair mechanisms and cell polarity changes, which often coexist with evasion mechanisms of the antiviral immune response. Viral agents also indirectly contribute to the development of cancer mainly through immunosuppression or chronic inflammation, but also through chronic antigenic stimulation. There is also evidence that viruses can modulate the malignant properties of an established tumor. In the present work, causation criteria for viruses and cancer will be described, as well as the viral agents that comply with these criteria in human tumors, their epidemiological and biological characteristics, the molecular mechanisms by which they induce cellular transformation and their associated cancers. Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available

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Open AccessCorrection Correction: Hollingworth, R.; Grand, R.J. Modulation of DNA Damage and Repair Pathways by Human Tumour Viruses. Viruses 2015, 7, 2542-2591
Viruses 2015, 7(6), 3201-3203; doi:10.3390/v7062767
Received: 9 June 2015 / Revised: 10 June 2015 / Accepted: 10 June 2015 / Published: 19 June 2015
PDF Full-text (72 KB) | HTML Full-text | XML Full-text
Abstract We have noted a number of errors in the references of this manuscript.[...] Full article
(This article belongs to the Special Issue Tumour Viruses) Print Edition available

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