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Genome Medicine Mar 2020Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and...
BACKGROUND
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC.
METHODS
In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a clinically implemented, next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome and software to detect integration sites and structure.
RESULTS
Sequencing from this approach revealed distinct integration junctions in the tumor genome and generated assemblies that strongly support a model of microhomology-initiated hybrid, virus-host, circular DNA intermediate that promotes focal amplification of host and viral DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Finally, comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival.
CONCLUSIONS
These results demonstrate the value of high-confidence virus detection for identifying molecular mechanisms of UV and viral oncogenesis in MCC. Furthermore, integrating these data with clinical data revealed features that could impact patient outcome and improve our understanding of MCC risk factors.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Merkel Cell; Child; DNA, Neoplasm; DNA, Viral; Female; Genetic Testing; Humans; Male; Middle Aged; Mutation; Polyomavirus; Polyomavirus Infections; Skin Neoplasms; Survival Analysis; Tumor Virus Infections
PubMed: 32188490
DOI: 10.1186/s13073-020-00727-4 -
Viruses May 2021Hamster polyomavirus (Mesocricetus auratus polyomavirus 1, HaPyV) was discovered as one of the first rodent polyomaviruses at the end of the 1960s in a colony of Syrian... (Review)
Review
Hamster polyomavirus (Mesocricetus auratus polyomavirus 1, HaPyV) was discovered as one of the first rodent polyomaviruses at the end of the 1960s in a colony of Syrian hamsters () affected by skin tumors. Natural HaPyV infections have been recorded in Syrian hamster colonies due to the occurrence of skin tumors and lymphomas. HaPyV infections of Syrian hamsters represent an important and pioneering tumor model. Experimental infections of Syrian hamsters of different colonies are still serving as model systems (e.g., mesothelioma). The observed phylogenetic relationship of HaPyV to murine polyomaviruses within the genus and the exclusive detection of other cricetid polyomaviruses, i.e., common vole (Microtus arvalis polyomavirus 1) and bank vole (Myodes glareolus polyomavirus 1) polyomaviruses, in the genus , must be considered with caution, as knowledge of rodent-associated polyomaviruses is still limited. The genome of HaPyV shows the typical organization of polyomaviruses with an early and a late transcriptional region. The early region encodes three tumor (T) antigens including a middle T antigen; the late region encodes three capsid proteins. The major capsid protein VP1 of HaPyV was established as a carrier for the generation of autologous, chimeric, and mosaic virus-like particles (VLPs) with a broad range of applications, e.g., for the production of epitope-specific antibodies. Autologous VLPs have been applied for entry and maturation studies of dendritic cells. The generation of chimeric and mosaic VLPs indicated the high flexibility of the VP1 carrier protein for the insertion of foreign sequences. The generation of pseudotype VLPs of original VP1 and VP2-foreign protein fusion can further enhance the applicability of this system. Future investigations should evaluate the evolutionary origin of HaPyV, monitor its occurrence in wildlife and Syrian hamster breeding, and prove its value for the generation of potential vaccine candidates and as a gene therapy vehicle.
Topics: Animals; Cell Transformation, Viral; Cricetinae; Disease Models, Animal; Disease Susceptibility; Genome, Viral; Genomics; Neoplasms; Polyomavirus; Polyomavirus Infections; Research; Rodentia; Tumor Virus Infections
PubMed: 34068409
DOI: 10.3390/v13050907 -
Transplant Infectious Disease : An... Dec 2020Trichodysplasia Spinulosa (TS) is a rare proliferative skin disease that occurs primarily in immunocompromised patients, specifically organ transplant recipients. TS is... (Review)
Review
Trichodysplasia Spinulosa (TS) is a rare proliferative skin disease that occurs primarily in immunocompromised patients, specifically organ transplant recipients. TS is characterized by uncontrolled inner root sheath cell proliferation and folliculocentric papular eruption that can progress to disfiguring leonine facies when left untreated. TS presents with distinct histological features including the presence of large eosinophilic, trichohyaline granules within hyperproliferating inner root sheath cells of the hair bulb. The discovery of the Trichodysplasia Spinulosa Polyomavirus (TSPyV) and recent studies highlighting the role of TSPyV tumor antigens in cell proliferation pathways have provided new insight into the mechanisms of TS development. In this review, we discuss the expansion of our understanding of TS, specifically over the past 5 years. We summarize novel cases of TS and recent developments in the mechanisms underlying TSPyV-mediated disease progression. We also evaluate advancements in diagnostic methods and treatment options. As the incidence of TS continues to rise, it is becoming critical for clinicians to understand the clinical features of TS and emerging research regarding pathogenesis and therapeutics for early treatment of this potentially disfiguring disease.
Topics: Antigens, Neoplasm; Cell Proliferation; Disease Progression; Hair Diseases; Humans; Immunocompromised Host; Polyomavirus; Polyomavirus Infections; Skin
PubMed: 32748541
DOI: 10.1111/tid.13434 -
Experimental and Clinical... Nov 2020The BK polyomavirus was isolated in 1971; it has been a significant risk factor for both graft dysfunction and failure in renal transplant recipients. So far, no... (Review)
Review
The BK polyomavirus was isolated in 1971; it has been a significant risk factor for both graft dysfunction and failure in renal transplant recipients. So far, no specific treatment option has been available for effective treatment or prophylaxis for BK virus infections. Although the use of heavy immunosuppression has been the main risk factor for BK virus infection, other risk factors are equally important, including elderly recipients, prior rejection episodes, male sex, human leukocyte antigen mismatching, prolonged cold ischemia time, pretransplant BK virus serostatus, and ureteral stenting. Regular follow-up for BK virus infections according to each institution's policy has been, so far, effective in detecting patients with BK virus viremia and consequently preventing allograft loss. The mainstay of management continues to be reduction of immunosuppression. However, newer options are providing new insights, such as cellular immunotherapy. In this review, we will address the diagnosis, screening, new diagnostic tools, and updated management of BK virus infections.
Topics: Adoptive Transfer; Antiviral Agents; BK Virus; Drug Substitution; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Immunosuppressive Agents; Immunotherapy; Kidney Transplantation; Opportunistic Infections; Polyomavirus Infections; Risk Assessment; Risk Factors; Treatment Outcome; Tumor Virus Infections
PubMed: 32552624
DOI: 10.6002/ect.2019.0254 -
Pediatric Transplantation Jun 2022
Topics: BK Virus; Female; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Diseases; Male; Polyomavirus Infections; Tumor Virus Infections
PubMed: 35429074
DOI: 10.1111/petr.14290 -
Journal of Neurology May 2022Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain-caused by human polyomavirus 2. It affects patients whose immune system... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral disease of the brain-caused by human polyomavirus 2. It affects patients whose immune system is compromised by a corresponding underlying disease or by drugs. Patients with an underlying lymphoproliferative disease have the worst prognosis with a mortality rate of up to 90%. Several therapeutic strategies have been proposed but failed to show any benefit so far. Therefore, the primary therapeutic strategy aims to reconstitute the impaired immune system to generate an effective endogenous antiviral response. Recently, anti-PD-1 antibodies and application of allogeneic virus-specific T cells demonstrated promising effects on the outcome in individual PML patients. This article aims to provide a detailed overview of the literature with a focus on these two treatment approaches.
Topics: Brain; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Prognosis
PubMed: 34994851
DOI: 10.1007/s00415-021-10952-5 -
Tumour Virus Research Dec 2022Human tumor viruses cause various human cancers that account for at least 15% of the global cancer burden. Among the currently identified human tumor viruses, two are... (Review)
Review
Human tumor viruses cause various human cancers that account for at least 15% of the global cancer burden. Among the currently identified human tumor viruses, two are small DNA tumor viruses: human papillomaviruses (HPVs) and Merkel cell polyomavirus (MCPyV). The study of small DNA tumor viruses (adenoviruses, polyomaviruses, and papillomaviruses) has facilitated several significant biological discoveries and established some of the first animal models of virus-associated cancers. The development and use of preclinical in vivo models to study HPVs and MCPyV and their role in human cancer is the focus of this review. Important considerations in the design of animal models of small DNA tumor virus infection and disease, including host range, cell tropism, choice of virus isolates, and the ability to recapitulate human disease, are presented. The types of infection-based and transgenic model strategies that are used to study HPVs and MCPyV, including their strengths and limitations, are also discussed. An overview of the current models that exist to study HPV and MCPyV infection and neoplastic disease are highlighted. These comparative models provide valuable platforms to study various aspects of virus-associated human disease and will continue to expand knowledge of human tumor viruses and their relationship with their hosts.
Topics: Animals; Humans; Merkel cell polyomavirus; Polyomavirus Infections; Tumor Virus Infections; Neoplasms; Polyomavirus; Oncogenic Viruses
PubMed: 35636683
DOI: 10.1016/j.tvr.2022.200239 -
International Journal of Molecular... Dec 2023Polyomaviruses are widespread, with BK viruses being most common in humans who require immunosuppression due to allotransplantation. Infection with BK polyomavirus (BKV)...
Polyomaviruses are widespread, with BK viruses being most common in humans who require immunosuppression due to allotransplantation. Infection with BK polyomavirus (BKV) may manifest as BK virus-associated nephropathy and hemorrhagic cystitis. Established diagnostic methods include the detection of polyomavirus in urine and blood by PCR and in tissue biopsies via immunohistochemistry. In this study, 79 patients with pathological renal retention parameters and acute kidney injury (AKI) were screened for BK polyomavirus replication by RNA extraction, reverse transcription, and virus-specific qPCR in urine sediment cells. A short fragment of the VP2 coding region was the target of qPCR amplification; patients with (n = 31) and without (n = 48) a history of renal transplantation were included. Urine sediment cell immunofluorescence staining for VP1 BK polyomavirus protein was performed using confocal microscopy. In 22 patients with acute renal injury, urinary sediment cells from 11 participants with kidney transplantation (KTX) and from 11 non-kidney transplanted patients (nonKTX) were positive for BK virus replication. BK virus copies were found more frequently in patients with AKI stage III (n = 14). Higher copy numbers were detected in KTX patients having experienced BK polyoma-nephropathy (BKPyVAN) in the past or diagnosed recently by histology (5.6 × 10-3.1 × 10). One patient developed BK viremia following delayed graft function (DGF) with BK virus-positive urine sediment. In nonKTX patients with BK copies, decoy cells were absent; however, positive staining of cells was found with epithelial morphology. Decoy cells were only found in KTX patients with BKPyVAN. In AKI, damage to the tubular epithelium itself may render the epithelial cells more permissive for polyoma replication. This non-invasive diagnostic approach to assess BK polyomavirus replication in urine sediment cells has the potential to identify KTX patients at risk for viremia and BKPyVAN during AKI. This method might serve as a valuable screening tool for close monitoring and tailored immunosuppression decisions.
Topics: Humans; BK Virus; Viremia; Kidney Transplantation; Kidney; Polyomavirus; Polyomavirus Infections; Acute Kidney Injury
PubMed: 38139342
DOI: 10.3390/ijms242417511 -
Viruses May 2022JC polyomavirus (JCPyV) is a small non-enveloped virus that establishes lifelong, persistent infection in most of the adult population. Immune-competent patients are... (Review)
Review
JC polyomavirus (JCPyV) is a small non-enveloped virus that establishes lifelong, persistent infection in most of the adult population. Immune-competent patients are generally asymptomatic, but immune-compromised and immune-suppressed patients are at risk for the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Studies with purified JCPyV found it undergoes receptor-dependent infectious entry requiring both lactoseries tetrasaccharide C (LSTc) attachment and 5-hydroxytryptamine type 2 entry receptors. Subsequent work discovered the major targets of JCPyV infection in the central nervous system (oligodendrocytes and astrocytes) do not express the required attachment receptor at detectable levels, virus could not bind these cells in tissue sections, and viral quasi-species harboring recurrent mutations in the binding pocket for attachment. While several research groups found evidence JCPyV can use novel receptors for infection, it was also discovered that extracellular vesicles (EVs) can mediate receptor independent JCPyV infection. Recent work also found JCPyV associated EVs include both exosomes and secretory autophagosomes. EVs effectively present a means of immune evasion and increased tissue tropism that complicates viral studies and anti-viral therapeutics. This review focuses on JCPyV infection mechanisms and EV associated and outlines key areas of study necessary to understand the interplay between virus and extracellular vesicles.
Topics: Astrocytes; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Neurodegenerative Diseases; Polyomavirus Infections
PubMed: 35746603
DOI: 10.3390/v14061130 -
Reviews in Medical Virology Nov 2021Human polyomaviruses (HPyVs) encompass more than 10 species infecting 30%-90% of the human population without significant illness. Proven HPyV diseases with documented... (Review)
Review
Human polyomaviruses (HPyVs) encompass more than 10 species infecting 30%-90% of the human population without significant illness. Proven HPyV diseases with documented histopathology affect primarily immunocompromised hosts with manifestations in brain, skin and renourinary tract such as polyomavirus-associated nephropathy (PyVAN), polyomavirus-associated haemorrhagic cystitis (PyVHC), polyomavirus-associated urothelial cancer (PyVUC), progressive multifocal leukoencephalopathy (PML), Merkel cell carcinoma (MCC), Trichodysplasia spinulosa (TS) and pruritic hyperproliferative keratinopathy. Although virus-specific immune control is the eventual goal of therapy and lasting cure, antiviral treatments are urgently needed in order to reduce or prevent HPyV diseases and thereby bridging the time needed to establish virus-specific immunity. However, the small dsDNA genome of only 5 kb of the non-enveloped HPyVs only encodes 5-7 viral proteins. Thus, HPyV replication relies heavily on host cell factors, thereby limiting both, number and type of specific virus-encoded antiviral targets. Lack of cost-effective high-throughput screening systems and relevant small animal models complicates the preclinical development. Current clinical studies are limited by small case numbers, poorly efficacious compounds and absence of proper randomized trial design. Here, we review preclinical and clinical studies that evaluated small molecules with presumed antiviral activity against HPyVs and provide an outlook regarding potential new antiviral strategies.
Topics: Antiviral Agents; DNA Viruses; Humans; Polyomavirus
PubMed: 33729628
DOI: 10.1002/rmv.2220