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New Frontiers in Small DNA Virus Research

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "General Virology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 25967

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Special Issue Editors

Dr. Katerina Strati

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Guest Editor

Department of Biological Sciences, University of Cyprus, Nicosia 1678, Cyprus
Interests: oncogenic viruses; papillomaviruses; virus-cell interactions; mouse models of infection and viral disease

Dr. Dohun Pyeon

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Guest Editor

Department of Microbiology and Molecular Genetics, Michigan State University, 567 Wilson Rd. BPS 4197, East Lansing, MI 48824-4320, USA
Interests: human papillomaviruses (HPV); tumor virology; virus-host interactions; antiviral immunity; antitumor immunity; immunotherapy

Special Issue Information

Dear Colleagues,

Although new technologies have significantly advanced our understanding of viruses and their interactions with host and environment in recent decades, we are continuously facing new challenges. The COVID-19 pandemic has shown us that our accumulated knowledge and experience become instrumental to cope with the urgent necessities of vaccine development. Nevertheless, the enormous casualties in one year of the pandemic has awoken us to the fact that we are far from well-prepared for future threats compounding current unsolved problems caused by viruses.

Studies in small DNA viruses including polyomavirus, papillomavirus, and adenovirus have led us to the breakthroughs of modern molecular and cellular biology and advanced our understanding of virally-mediated diseases (cancers, autoimmunity, etc.). For example, SV40 research opened the door to discoveries of basic molecular (transcriptional regulation) and oncogenic (tumor suppressors and tyrosine kinases) mechanisms. In addition, while the HPV and HBV research brought us the two most successful cancer vaccines, adenovirus is being used as one of the most popular viral vectors in gene therapies and vaccines, including the COVID-19 vaccines.

To continue our success and usher a new chapter in small DNA virus research, we would like to invite you to share your recent findings or perspectives on big questions and future directions, including but not limited to: viral oncogenesis, commensalism and pathogenesis, host immunity, host cell stemness, epigenetic dysregulation, noncoding RNAs, metabolism, viral vectors, and new experimental models.

Dr. Katerina Strati
Dr. Dohun Pyeon
Guest Editors

Manuscript Submission Information

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Keywords

Papillomavirus
HPV
polyomavirus
cervical cancer
head and neck cancer
oral cancer
skin cancer
anal cancer
innate immunity
immune evasion
immunotherapy
noncoding RNA
circular RNA
metabolism
small DNA virus
commensalism
virome
tumor virus
carcinogenesis
oncogenesis
frontier
chromatin
epigenetics
stem cell
virus entry
cancer vaccine
persistent infection
experimental model
new technology
AdV; adenovirus
polyomavirus
mMuPV1
HBV
polyomavirus
JC virus
BK virus
viral vectors
Merkel cell polyoma virus

Published Papers (11 papers)

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Editorial

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3 pages, 178 KiB

Open AccessEditorial

Special Issue “New Frontiers in Small DNA Virus Research”

by Katerina Strati and Dohun Pyeon

Viruses 2023, 15(1), 259; https://doi.org/10.3390/v15010259 - 16 Jan 2023

Viewed by 1394

Abstract

Scientific progress in understanding, preventing, treating, and managing viral infections and associated diseases exemplifies the extent to which research on small DNA tumor viruses has impacted human health [...] Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

Research

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17 pages, 2543 KiB

Open AccessArticle

Global Transcriptome Analyses of Cellular and Viral mRNAs during HAdV-C5 Infection Highlight New Aspects of Viral mRNA Biogenesis and Cytoplasmic Viral mRNA Accumulations

by Margarita Valdés Alemán, Luca D. Bertzbach, Thomas Speiseder, Wing Hang Ip, Ramón A. González and Thomas Dobner

Viruses 2022, 14(11), 2428; https://doi.org/10.3390/v14112428 - 1 Nov 2022

Cited by 4 | Viewed by 1828

Abstract

It is well established that human adenoviruses such as species C, types 2 and 5 (HAdV-C2 and HAdV-C5), induce a nearly complete shutoff of host-cell protein synthesis in the infected cell, simultaneously directing very efficient production of viral proteins. Such preferential expression of viral over cellular genes is thought to be controlled by selective nucleocytoplasmic export and translation of viral mRNA. While detailed knowledge of the regulatory mechanisms responsible for the translation of viral mRNA is available, the viral or cellular mechanisms of mRNA biogenesis are not completely understood. To identify parameters that control the differential export of viral and cellular mRNAs, we performed global transcriptome analyses (RNAseq) and monitored temporal nucleocytoplasmic partitioning of viral and cellular mRNAs during HAdV-C5 infection of A549 cells. Our analyses confirmed previously reported features of the viral mRNA expression program, as a clear shift in viral early to late mRNA accumulation was observed upon transition from the early to the late phase of viral replication. The progression into the late phase of infection, however, did not result in abrogation of cellular mRNA export; rather, viral late mRNAs outnumbered viral early and most cellular mRNAs by several orders of magnitude during the late phase, revealing that viral late mRNAs are not selectively exported but outcompete cellular mRNA biogenesis. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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13 pages, 2585 KiB

Open AccessArticle

Human Virome in Cervix Controlled by the Domination of Human Papillomavirus

by Thanayod Sasivimolrattana, Wasun Chantratita, Insee Sensorn, Arkom Chaiwongkot, Shina Oranratanaphan and Parvapan Bhattarakosol

Viruses 2022, 14(9), 2066; https://doi.org/10.3390/v14092066 - 17 Sep 2022

Cited by 3 | Viewed by 2121

Abstract

Although other co-viral infections could also be considered influencing factors, cervical human papillomavirus (HPV) infection is the main cause of cervical cancer. Metagenomics have been employed in the NGS era to study the microbial community in each habitat. Thus, in this investigation, virome capture sequencing was used to examine the virome composition in the HPV-infected cervix. Based on the amount of HPV present in each sample, the results revealed that the cervical virome of HPV-infected individuals could be split into two categories: HPV-dominated (HD; ≥60%) and non-HPV-dominated (NHD; <60%). Cervical samples contained traces of several human viral species, including the molluscum contagiosum virus (MCV), human herpesvirus 4 (HHV4), torque teno virus (TTV), and influenza A virus. When compared to the HD group, the NHD group had a higher abundance of several viruses. Human viral diversity appears to be influenced by HPV dominance. This is the first proof that the diversity of human viruses in the cervix is impacted by HPV abundance. However, more research is required to determine whether human viral variety and the emergence of cancer are related. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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15 pages, 2337 KiB

Open AccessArticle

Therapeutic Potential of 5′-Methylschweinfurthin G in Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma

by Emily J. Koubek, Jillian S. Weissenrieder, Luz E. Ortiz, Nnenna Nwogu, Alexander M. Pham, J. Dylan Weissenkampen, Jessie L. Reed, Jeffrey D. Neighbors, Raymond J. Hohl and Hyun Jin Kwun

Viruses 2022, 14(9), 1848; https://doi.org/10.3390/v14091848 - 23 Aug 2022

Cited by 2 | Viewed by 2013

Abstract

Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer predominantly caused by the human Merkel cell polyomavirus (MCPyV). Treatment for MCC includes excision and radiotherapy of local disease, and chemotherapy or immunotherapy for metastatic disease. The schweinfurthin family of natural compounds previously displayed potent and selective growth inhibitory activity against the NCI-60 panel of human-derived cancer cell lines. Here, we investigated the impact of schweinfurthin on human MCC cell lines. Treatment with the schweinfurthin analog, 5′-methylschweinfurth G (MeSG also known as TTI-3114), impaired metabolic activity through induction of an apoptotic pathway. MeSG also selectively inhibited PI3K/AKT and MAPK/ERK pathways in the MCPyV-positive MCC cell line, MS-1. Interestingly, expression of the MCPyV small T (sT) oncogene selectively sensitizes mouse embryonic fibroblasts to MeSG. These results suggest that the schweinfurthin family of compounds display promising potential as a novel therapeutic option for virus-induced MCCs. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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11 pages, 2715 KiB

Open AccessArticle

MmuPV1-Induced Cutaneous Squamous Cell Carcinoma Arises Preferentially from Lgr5+ Epithelial Progenitor Cells

by Ruben Moreno, Darya Buehler and Paul F. Lambert

Viruses 2022, 14(8), 1751; https://doi.org/10.3390/v14081751 - 11 Aug 2022

Cited by 2 | Viewed by 1786

Abstract

Murine papillomavirus, MmuPV1, causes natural infections in laboratory mice that can progress to squamous cell carcinoma (SCC) making it a useful preclinical model to study the role of papillomaviruses in cancer. Papillomavirus can infect cells within hair follicles, which contain multiple epithelial progenitor cell populations, including Lgr5+ progenitors, and transgenic mice expressing human papillomavirus oncogenes develop tumors derived from Lgr5 progenitors. We therefore tested the hypothesis that Lgr5+ progenitors contribute to neoplastic lesions arising in skins infected with MmuPV1 by performing lineage tracing experiments. Ears of 6–8-week-old Lgr5-eGFP-IRES-CreERT2/Rosa26LSLtdTomato mice were treated topically with 4-OH Tamoxifen to label Lgr5+ progenitor cells and their progeny with tdTomato and, 72 h later, infected with MmuPV1. Four months post-infection, tissue at the infection site was harvested for histopathological analysis and immunofluorescence to determine the percentage of tdTomato+ cells within the epithelial lesions caused by MmuPV1. Squamous cell dysplasia showed a low percentage of tdTomato+ cells (7%), indicating that it arises primarily from non-Lgr5 progenitor cells. In contrast, cutaneous SCC (cSCC) was substantially more positive for tdTomato+ cells (42%), indicating that cSCCs preferentially arise from Lgr5+ progenitors. Biomarker analyses of dysplasia vs. cSCC revealed further differences consistent with cSCC arising from LGR5+ progenitor cells. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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17 pages, 1050 KiB

Open AccessArticle

Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection

by Long-Bin Jeng, Tsai-Chung Li, Shih-Chao Hsu and Chiao-Fang Teng

Viruses 2022, 14(6), 1346; https://doi.org/10.3390/v14061346 - 20 Jun 2022

Cited by 2 | Viewed by 2359

Abstract

Although surgical resection is available as a potentially curative therapy for hepatocellular carcinoma (HCC), high recurrence of HCC after surgery remains a serious obstacle for long-term patient survival. Therefore, the discovery of valuable prognostic biomarkers for HCC recurrence is urgently needed. Pre-S2 mutant is a mutant form of hepatitis B virus (HBV) large surface protein which is expressed from the HBV surface gene harboring deletion mutations spanning the pre-S2 gene segment. Pre-S2 mutant-positive HCC patients have been regarded as a high-risk population of HCC recurrence after resection surgery and display increased immune checkpoint programmed death ligand 1 (PD-L1) expression and pro-tumor regulatory T cells (Tregs) infiltration in tumor tissues. In this study, the association of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues with post-operative HCC recurrence in pre-S2 mutant-positive HCC patients was evaluated. We found that patients with pre-S2 mutant in combination with higher levels of PD-L1 expression and Tregs infiltration in tumor tissues were independently associated with a higher risk of HCC recurrence (hazard ratio, 4.109; p value = 0.0011) and poorer recurrence-free survival (median, 8.2 versus 18.0 months; p value = 0.0004) than those of patients with either one or two of these three biomarkers. Furthermore, a combination of pre-S2 mutant, intra-tumoral PD-L1 expression, and tumor-infiltrating Tregs exhibited superior performance in identifying patients at a higher risk of HCC recurrence (area under the receiver operating characteristic curve, 0.8400). Collectively, this study suggests that higher levels of PD-L1 expression and Tregs infiltration in tumor tissues predicted a higher risk of HCC recurrence in pre-S2 mutant-positive HCC patients after curative surgical resection. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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Review

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16 pages, 1020 KiB

Open AccessReview

Mechanistic Contributions of lncRNAs to Cellular Signaling Pathways Crucial to the Lifecycle of Human Papillomaviruses

by Warda Arman and Karl Munger

Viruses 2022, 14(11), 2439; https://doi.org/10.3390/v14112439 - 3 Nov 2022

Cited by 2 | Viewed by 1862

Abstract

Papillomaviruses are ubiquitous epitheliotropic viruses with double-stranded circular DNA genomes of approximately 8000 base pairs. The viral life cycle is somewhat unusual in that these viruses can establish persistent infections in the mitotically active basal epithelial cells that they initially infect. High-level viral genome replication (“genome amplification”), the expression of capsid proteins, and the formation of infectious progeny are restricted to terminally differentiated cells where genomes are synthesized at replication factories at sites of double-strand DNA breaks. To establish persistent infections, papillomaviruses need to retain the basal cell identity of the initially infected cells and restrain and delay their epithelial differentiation program. To enable high-level viral genome replication, papillomaviruses also need to hold the inherently growth-arrested terminally differentiated cells in a replication-competent state. To provide ample sites for viral genome synthesis, they target the DNA damage and repair machinery. Studies focusing on delineating cellular factors that are targeted by papillomaviruses may aid the development of antivirals. Whilst most of the current research efforts focus on protein targets, the majority of the human transcriptome consists of noncoding RNAs. This review focuses on one specific class of noncoding RNAs, long noncoding RNAs (lncRNAs), and summarizes work on lncRNAs that may regulate the cellular processes that are subverted by papillomavirus to enable persistent infections and progeny synthesis. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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26 pages, 1749 KiB

Open AccessReview

Current In Vitro and In Vivo Models to Study MCPyV-Associated MCC

by Amanda S. W. Loke, Paul F. Lambert and Megan E. Spurgeon

Viruses 2022, 14(10), 2204; https://doi.org/10.3390/v14102204 - 7 Oct 2022

Cited by 5 | Viewed by 2171

Abstract

Merkel cell polyomavirus (MCPyV) is the only human polyomavirus currently known to cause human cancer. MCPyV is believed to be an etiological factor in at least 80% of cases of the rare but aggressive skin malignancy Merkel cell carcinoma (MCC). In these MCPyV+ MCC tumors, clonal integration of the viral genome results in the continued expression of two viral proteins: the viral small T antigen (ST) and a truncated form of the viral large T antigen. The oncogenic potential of MCPyV and the functional properties of the viral T antigens that contribute to neoplasia are becoming increasingly well-characterized with the recent development of model systems that recapitulate the biology of MCPyV+ MCC. In this review, we summarize our understanding of MCPyV and its role in MCC, followed by the current state of both in vitro and in vivo model systems used to study MCPyV and its contribution to carcinogenesis. We also highlight the remaining challenges within the field and the major considerations related to the ongoing development of in vitro and in vivo models of MCPyV+ MCC. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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36 pages, 1435 KiB

Open AccessReview

Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B

by Manasa Suresh and Stephan Menne

Viruses 2022, 14(8), 1711; https://doi.org/10.3390/v14081711 - 3 Aug 2022

Cited by 4 | Viewed by 3277

Abstract

Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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19 pages, 1962 KiB

Open AccessReview

Harnessing Human Papillomavirus’ Natural Tropism to Target Tumors

by Rhonda C. Kines and John T. Schiller

Viruses 2022, 14(8), 1656; https://doi.org/10.3390/v14081656 - 28 Jul 2022

Cited by 7 | Viewed by 3816

Abstract

Human papillomaviruses (HPV) are small non-enveloped DNA tumor viruses established as the primary etiological agent for the development of cervical cancer. Decades of research have elucidated HPV’s primary attachment factor to be heparan sulfate proteoglycans (HSPG). Importantly, wounding and exposure of the epithelial basement membrane was found to be pivotal for efficient attachment and infection of HPV in vivo. Sulfation patterns on HSPG’s become modified at the site of wounds as they serve an important role promoting tissue healing, cell proliferation and neovascularization and it is these modifications recognized by HPV. Analogous HSPG modification patterns can be found on tumor cells as they too require the aforementioned processes to grow and metastasize. Although targeting tumor associated HSPG is not a novel concept, the use of HPV to target and treat tumors has only been realized in recent years. The work herein describes how decades of basic HPV research has culminated in the rational design of an HPV-based virus-like infrared light activated dye conjugate for the treatment of choroidal melanoma. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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Other

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8 pages, 804 KiB

Open AccessCase Report

Belatacept as a Treatment Option in Patients with Severe BK Polyomavirus Infection and High Immunological Risk—Walking a Tightrope between Viral Control and Prevention of Rejection

by Ulrich Jehn, Sami Siam, Vanessa Wiening, Hermann Pavenstädt and Stefan Reuter

Viruses 2022, 14(5), 1005; https://doi.org/10.3390/v14051005 - 9 May 2022

Cited by 2 | Viewed by 1867

Abstract

Balancing the immune system with immunosuppressive treatment is essential in kidney transplant recipients to avoid allograft rejection on the one hand and infectious complications on the other. BK polyomavirus nephropathy (BKPyVAN) is a viral complication that seriously threatens kidney allograft survival. Therefore, the main treatment strategy is to reduce immunosuppression, but this is associated with an increased rejection risk. Belatacept is an immunosuppressant that acts by blocking the CD80/86-CD28 co-stimulatory pathway of effector T-cells with marked effects on the humoral response. However, when compared with calcineurin-inhibitors (CNI), the cellular rejection rate is higher. With this in mind, we hypothesized that belatacept could be used as rescue therapy in severely BKPyV-affected patients with high immunological risk. We present three cases of patients with BKPyVAN-associated complications and donor-specific antibodies (DSA) and one patient who developed T-cell-mediated rejection after a reduction in immunosuppression in response to BKPyVAN. Patients were switched to a belatacept-based immunosuppressive regimen and showed significantly improved viral control and stabilized graft function. The cases presented here suggest that belatacept is a potential treatment option in the complicated situation of refractory BKPyV infection in patients with high immunological risk. Full article

(This article belongs to the Special Issue New Frontiers in Small DNA Virus Research)

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