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1.
Viruses ; 13(5)2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-34068409

RESUMEN

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 (Mesocricetus auratus) 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 Alphapolyomavirus, 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 Betapolyomavirus, 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.


Asunto(s)
Infecciones por Polyomavirus/virología , Poliomavirus/fisiología , Investigación/tendencias , Animales , Transformación Celular Viral , Cricetinae , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Genoma Viral , Genómica/métodos , Neoplasias/etiología , Neoplasias/patología , Poliomavirus/clasificación , Poliomavirus/ultraestructura , Infecciones por Polyomavirus/complicaciones , Roedores/virología , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/virología
2.
PLoS Pathog ; 17(4): e1009560, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33930088

RESUMEN

Herpes-Simplex Virus 1 (HSV-1) infects most humans when they are young, sometimes with fatal consequences. Gene expression occurs in a temporal order upon lytic HSV-1 infection: immediate early (IE) genes are expressed, then early (E) genes, followed by late (L) genes. During this infection cycle, the HSV-1 genome has the potential for exposure to APOBEC3 (A3) proteins, a family of cytidine deaminases that cause C>U mutations on single-stranded DNA (ssDNA), often resulting in a C>T transition. We developed a computational model for the mutational pressure of A3 on the lytic cycle of HSV-1 to determine which viral kinetic gene class is most vulnerable to A3 mutations. Using in silico stochastic methods, we simulated the infectious cycle under varying intensities of A3 mutational pressure. We found that the IE and E genes are more vulnerable to A3 than L genes. We validated this model by analyzing the A3 evolutionary footprints in 25 HSV-1 isolates. We find that IE and E genes have evolved to underrepresent A3 hotspot motifs more so than L genes, consistent with greater selection pressure on IE and E genes. We extend this model to two-step infections, such as those of polyomavirus, and find that the same pattern holds for over 25 human Polyomavirus (HPyVs) genomes. Genes expressed earlier during infection are more vulnerable to mutations than those expressed later.


Asunto(s)
Desaminasas APOBEC/fisiología , Herpesvirus Humano 1/fisiología , Proteínas Inmediatas-Precoces/genética , Mutagénesis/genética , Poliomavirus/fisiología , Algoritmos , Regulación Viral de la Expresión Génica , Genes Inmediatos-Precoces/genética , Herpes Simple/genética , Herpes Simple/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidad , Interacciones Huésped-Patógeno/genética , Humanos , Modelos Teóricos , Mutación , Poliomavirus/genética , Poliomavirus/patogenicidad , Infecciones por Polyomavirus/genética , Infecciones por Polyomavirus/virología , Replicación Viral/genética
3.
Curr Opin Virol ; 47: 95-105, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33690104

RESUMEN

Polyomaviruses are mostly non-pathogenic, yet some can cause human disease especially under conditions of immunosuppression, including JC, BK, and Merkel cell polyomaviruses. Direct interactions between viruses and the host early during infection dictate the outcome of disease, many of which remain enigmatic. However, significant work in recent years has contributed to our understanding of how this virus family establishes an infection, largely due to advances made for animal polyomaviruses murine and SV40. Here we summarize the major findings that have contributed to our understanding of polyomavirus entry, trafficking, disassembly, signaling, and immune evasion during the infectious process and highlight major unknowns in these processes that are open areas of study.


Asunto(s)
Poliomavirus/fisiología , Internalización del Virus , Animales , Núcleo Celular/virología , Retículo Endoplásmico/virología , Endosomas/virología , Humanos , Evasión Inmune , Transducción de Señal , Acoplamiento Viral
4.
Viruses ; 13(1)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477927

RESUMEN

"Definitive" biopsy proven polyomavirus nephropathy (PyVN), usually caused by BK polyomavirus (BKPyV), remains a significant infection of kidney transplants. Diagnosis depends upon an allograft biopsy and outcome depends upon early intervention. Here, we report data on a non-invasive biomarker for PyVN, the urinary PyV-Haufen test. Test results were compared to those of conventional laboratory assays targeting PyV replication, i.e., BKPy-viremia, -viruria and urinary decoy cell shedding. Of 809 kidney transplant recipients, 228 (28%) showed PyV replication with decoy cell shedding and/or BKPy-viremia by quantitative PCR; only a subset of 81/228 (36%) showed "definitive" PyVN. Sensitivity and specificity for identifying patients with PyVN was: 100% and 98%, respectively, urinary PyV-Haufen test; 50% and 54%, respectively, urinary decoy cell shedding; 97% and 32%, respectively, BKPy-viremia with cut-off of ≥250 viral copies/mL; 66% and 80%, respectively, for BKPy-viremia ≥104 viral copies/mL. The PyV-Haufen test showed a very strong correlation with the severity of PyVN (Spearman's ρ = 0.84) and the Banff PyVN disease classes (p < 0.001). In comparison, BKPy-viremia and -viruria levels by PCR displayed modest correlations with PyVN severity (Spearman's ρ = 0.35 and 0.36, respectively) and were not significantly associated with disease classes. No association was found between decoy cell shedding and PyVN severity or disease classes. Pilot data demonstrated that PyVN resolution with decreasing Banff pvl-scores was reflected by a gradual decrease in PyV-Haufen shedding; such a tight association was not noted for BKPy-viremia. In conclusion, urinary PyV-Haufen testing is a highly specific, non-invasive method to accurately diagnose patients with "definitive" PyVN and to optimize patient management. Assay specifics are discussed.


Asunto(s)
Enfermedades Renales/diagnóstico , Enfermedades Renales/etiología , Infecciones por Polyomavirus/complicaciones , Infecciones por Polyomavirus/virología , Poliomavirus/fisiología , Urinálisis/métodos , Biomarcadores , Biopsia , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Inmunohistoquímica , Enfermedades Renales/terapia , Enfermedades Renales/orina , Trasplante de Riñón , Reacción en Cadena de la Polimerasa , Poliomavirus/ultraestructura , Infecciones por Polyomavirus/diagnóstico , Pronóstico , Sensibilidad y Especificidad , Resultado del Tratamiento , Urinálisis/normas , Carga Viral
5.
Avian Pathol ; 50(1): 41-51, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33021105

RESUMEN

Goose haemorrhagic polyomavirus (GHPV) is the aetiological agent of haemorrhagic nephritis enteritis of geese (HNEG), a fatal disease that impacts geese and has been recorded only in Europe. The present study describes the first clinical cases of HNEG in Taiwan and the phylogenesis of Taiwanese GHPV, and it elucidates the pathogenesis of GHPV infection using in situ hybridization (ISH). The genomes of Taiwanese GHPV were highly similar to the previously reported strains. The diseased geese showed various degrees of vascular damage, especially in the digestive tract. The affected geese in the early stage showed transmural haemorrhagic enteritis in the intestine. In the middle to late stages, the most obvious lesion was hypoxic necrosis of renal tubules around intralobular central veins. Mineralization deposited in the kidney and systemic gout were also found. ISH revealed GHPV DNA in the vascular endothelial cells throughout the body, but not in the parenchymal cells of organs. Accordingly, the pathogenesis of GHPV infection was consistent with viral tropism in the endothelial cells. Specific attack of vascular endothelium by GHPV resulted in endothelial cell necrosis and subsequent increases of blood vessel permeability, as well as secondary circulation disorders, such as oedema, haemorrhage, and ischaemic necrosis in the adjacent parenchyma. RESEARCH HIGHLIGHTS Cell tropism of GHPV is determined by in situ hybridization. The tropism results in vascular dysfunction and subsequent pathobiology. Haemorrhagic nephritis and enteritis of geese described outside Europe for the first time.


Asunto(s)
Gansos/virología , Infecciones por Polyomavirus/veterinaria , Poliomavirus/fisiología , Enfermedades de las Aves de Corral/virología , Animales , Células Endoteliales/patología , Células Endoteliales/virología , Enteritis/veterinaria , Hemorragia/veterinaria , Hibridación in Situ/veterinaria , Intestinos/patología , Intestinos/virología , Riñón/patología , Riñón/virología , Nefritis/veterinaria , Filogenia , Poliomavirus/genética , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/patología , Infecciones por Polyomavirus/virología , Enfermedades de las Aves de Corral/epidemiología , Enfermedades de las Aves de Corral/patología , Taiwán/epidemiología , Tropismo Viral
6.
Viruses ; 12(11)2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33182443

RESUMEN

Human Polyomavirus (HPyV) infections are common, ranging from 60% to 100%. In kidney transplant (KTx) recipients, HPyVs have been associated with allograft nephropathy, progressive multifocal leukoencephalopathy, and skin cancer. Whether such complications are caused by viral reactivation or primary infection transmitted by the donor remains debated. This study aimed to investigate the replication pattern and genomic characterization of BK Polyomavirus (BKPyV), JC Polyomavirus (JCPyV), and Merkel Cell Polyomavirus (MCPyV) infections in KTx. Urine samples from 57 KTx donor/recipient pairs were collected immediately before organ retrieval/transplant and periodically up to post-operative day 540. Specimens were tested for the presence of BKPyV, JCPyV, and MCPyV genome by virus-specific Real-Time PCR and molecularly characterized. HPyVs genome was detected in 49.1% of donors and 77.2% of recipients. Sequences analysis revealed the archetypal strain for JCPyV, TU and Dunlop strains for BKPyV, and IIa-2 strain for MCPyV. VP1 genotyping showed a high frequency for JCPyV genotype 1 and BKPyV genotype I. Our experience demonstrates that after KTx, HPyVs genome remains stable over time with no emergence of quasi-species. HPyVs strains isolated in donor/recipient pairs are mostly identical, suggesting that viruses detected in the recipient may be transmitted by the allograft.


Asunto(s)
Genoma Viral , Trasplante de Riñón , Infecciones por Polyomavirus/orina , Poliomavirus/genética , Replicación Viral , Adulto , Anciano , Virus BK/genética , Virus BK/fisiología , Femenino , Genómica , Humanos , Virus JC/genética , Virus JC/fisiología , Masculino , Poliomavirus de Células de Merkel/genética , Poliomavirus de Células de Merkel/fisiología , Persona de Mediana Edad , Poliomavirus/clasificación , Poliomavirus/fisiología , Infecciones por Polyomavirus/virología , Estudios Prospectivos , Donantes de Tejidos , Receptores de Trasplantes
7.
Biochem Soc Trans ; 48(5): 2173-2184, 2020 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-33119046

RESUMEN

The endoplasmic reticulum (ER), with its expansive membranous system and a vast network of chaperones, enzymes, sensors, and ion channels, orchestrates diverse cellular functions, ranging from protein synthesis, folding, secretion, and degradation to lipid biogenesis and calcium homeostasis. Strikingly, some of the functions of the ER are exploited by viruses to promote their life cycles. During entry, viruses must penetrate a host membrane and reach an intracellular destination to express and replicate their genomes. These events lead to the assembly of new viral progenies that exit the host cell, thereby initiating further rounds of infection. In this review, we highlight how three distinct viruses - polyomavirus, flavivirus, and coronavirus - co-opt key functions of the ER to cause infection. We anticipate that illuminating this virus-ER interplay will provide rational therapeutic approaches to combat the virus-induced diseases.


Asunto(s)
Coronavirus/fisiología , Retículo Endoplásmico/metabolismo , Flavivirus/fisiología , Interacciones Huésped-Patógeno , Poliomavirus/fisiología , Humanos , Chaperonas Moleculares/metabolismo , Virosis/metabolismo , Virosis/prevención & control , Internalización del Virus , Replicación Viral
8.
Viruses ; 12(10)2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33023278

RESUMEN

During polyomavirus (PyV) infection, host proteins localize to subnuclear domains, termed viral replication centers (VRCs), to mediate viral genome replication. Although the protein composition and spatial organization of VRCs have been described using high-resolution immunofluorescence microscopy, little is known about the temporal dynamics of VRC formation over the course of infection. We used live cell fluorescence microscopy to analyze VRC formation during murine PyV (MuPyV) infection of a mouse fibroblast cell line that constitutively expresses a GFP-tagged replication protein A complex subunit (GFP-RPA32). The RPA complex forms a heterotrimer (RPA70/32/14) that regulates cellular DNA replication and repair and is a known VRC component. We validated previous observations that GFP-RPA32 relocalized to sites of cellular DNA damage in uninfected cells and to VRCs in MuPyV-infected cells. We then used GFP-RPA32 as a marker of VRC formation and expansion during live cell microscopy of infected cells. VRC formation occurred at variable times post-infection, but the rate of VRC expansion was similar between cells. Additionally, we found that the early viral protein, small TAg (ST), was required for VRC expansion but not VRC formation, consistent with the role of ST in promoting efficient vDNA replication. These results demonstrate the dynamic nature of VRCs over the course of infection and establish an approach for analyzing viral replication in live cells.


Asunto(s)
Microscopía/métodos , Infecciones por Polyomavirus/virología , Poliomavirus/fisiología , Proteína de Replicación A/metabolismo , Replicación Viral/fisiología , Animales , Línea Celular/citología , Daño del ADN , Replicación del ADN , ADN Viral/genética , Genoma Viral , Cinética , Ratones , Ratones Endogámicos C57BL , Poliomavirus/genética , Infecciones por Polyomavirus/patología , Proteína de Replicación A/genética
9.
Viruses ; 12(10)2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-33092168

RESUMEN

Polyomaviruses are small, non-enveloped DNA tumor viruses that cause serious disease in immunosuppressed people, including progressive multifocal leukoencephalopathy (PML) in patients infected with JC polyomavirus, but the molecular events mediating polyomavirus entry are poorly understood. Through genetic knockdown approaches, we identified phosphoinositide 3'-kinase γ (PI3Kγ) and its regulatory subunit PIK3R5 as cellular proteins that facilitate infection of human SVG-A glial cells by JCPyV. PI3Kα appears less important for polyomavirus infection than PI3Kγ. CRISPR/Cas9-mediated knockout of PIK3R5 or PI3Kγ inhibited infection by authentic JCPyV and by JC pseudovirus. PI3Kγ knockout also inhibited infection by BK and Merkel Cell pseudoviruses, other pathogenic human polyomaviruses, and SV40, an important model polyomavirus. Reintroduction of the wild-type PI3Kγ gene into the PI3Kγ knock-out SVG-A cells rescued the JCPyV infection defect. Disruption of the PI3Kγ pathway did not block binding of JCPyV to cells or virus internalization, implying that PI3Kγ facilitates some intracellular step(s) of infection. These results imply that agents that inhibit PI3Kγ signaling may have a role in managing polyomavirus infections.


Asunto(s)
Virus JC/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Infecciones por Polyomavirus , Poliomavirus/fisiología , Internalización del Virus , Línea Celular , Humanos , Leucoencefalopatía Multifocal Progresiva/virología , Neuroglía/enzimología , Neuroglía/virología , Fosfatidilinositoles/metabolismo , Infecciones por Polyomavirus/enzimología , Infecciones por Polyomavirus/virología
10.
Transbound Emerg Dis ; 67(6): 2602-2608, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32374515

RESUMEN

Goose haemorrhagic polyomavirus (GHPV, or Anser anser polyomavirus 1) is a small dsDNA virus of the Polyomaviridae family. The virus infects the internal organs causing haemorrhagic nephritis and enteritis of geese that may be fatal for goslings. In this study, GHPV positivity was examined in goose and duck samples collected in Hungary between 2005 and 2019. In this period, 384 of the investigated 1,111 specimens were diagnosed as GHPV-positive by PCR assay. Twenty-two GHPV genomes were sequenced and subjected to phylogenetic and evolutionary analysis. Based on the sequence data, the mean evolutionary rates were estimated 6.57 × 10-6 -5.82 × 10-5  s/s/y for both GHPV complete genomes and individual genes, with negative selection acting on each gene. When GHPV VP1 sequences originating from wild birds were also included in the analyses, the nt and aa mutations inflated the substitution rate to 1.54 × 10-4  s/s/y that may imply adaptation of the virus to novel host species. Our data suggested the co-circulation of various GHPV strains in Hungarian goose farms; the source of these may be persistently infected domesticated or migratory wild birds. Detection and characterization of GHPV in wild birds and domestic waterfowls may help to elaborate new strategies for more effective disease control and prevention.


Asunto(s)
Patos , Gansos , Infecciones por Polyomavirus/veterinaria , Poliomavirus/fisiología , Enfermedades de las Aves de Corral/epidemiología , Infecciones Tumorales por Virus/veterinaria , Animales , Hungría/epidemiología , Epidemiología Molecular , Filogenia , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/virología , Enfermedades de las Aves de Corral/virología , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/virología
11.
Antiviral Res ; 179: 104819, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32389733

RESUMEN

During virus entry, members of the Polyomaviridae transit the endolysosomal network en route to the endoplasmic reticulum (ER), from which degraded capsids escape into the cytoplasm and enter the nucleus. Emerging evidence suggests that viruses require both endosomal acidification and the correct ionic balance of K+ and Ca2+ ions in endosomes for correct virus trafficking and genome release. Here, using two polyomaviruses with different capsid architectures, namely Simian virus 40 (SV40) and Merkel cell polyomavirus (MCPyV), we describe methods to rapidly quantify virus infection using IncuCyte ZOOM imaging analysis, and use this system to investigate the role of both K+ and Ca2+ channels during the early stages of virus entry. Using broad spectrum blockers of both K+ and Ca2+ channels to specifically target host cell ion channel functionality, we show that MCPyV, but not SV40 can be inhibited by K+ channel modulators, whilst both viruses are restricted by the broad spectrum Ca2+ channel inhibitor verapamil. Using a panel of more specific Ca2+ blockers, we show that both MCPyV and SV40 are dependent on the activity of two-pore Ca2+ channels (TPCs), as the TPC-specific blocker tetrandrine prevented capsid disassembly and nuclear transport required for virus entry. We therefore reveal a novel target to restrict the entry of polyomaviruses, which given the known role of TPCs during endolysosomal-ER fusion, is likely to be applicable to other viruses that transit this pathway.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Endosomas/fisiología , Poliomavirus/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Internalización del Virus/efectos de los fármacos , Animales , Bencilisoquinolinas/farmacología , Línea Celular , Movimiento Celular , Chlorocebus aethiops , Descubrimiento de Drogas , Endosomas/virología , Células HEK293 , Humanos , Poliomavirus de Células de Merkel/efectos de los fármacos , Poliomavirus de Células de Merkel/fisiología , Poliomavirus/fisiología , Virus 40 de los Simios/efectos de los fármacos , Virus 40 de los Simios/fisiología , Verapamilo/farmacología , Células Vero
12.
Viruses ; 12(6)2020 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-32471033

RESUMEN

Increasing evidence suggests that human viruses can hijack extracellular vesicles (EVs) to deliver proteins, mRNAs, microRNAs (miRNAs) and whole viral particles during viral persistence in the host. Human polyomavirus (PyV) miRNAs, which downregulate large T-antigen expression and target host factors, help the virus escape immune elimination and may have roles in the success of viral persistence/replication and the development of diseases. In this context, several investigations have detected PyV miRNAs in EVs obtained from cell culture supernatants after viral infection, demonstrating the ability of these vesicles to deliver miRNAs to uninfected cells, potentially counteracting new viral infection. Additionally, PyV miRNAs have been identified in EVs derived from the biological fluids of clinical samples obtained from patients with or at risk of severe PyV-associated diseases and from asymptomatic control healthy subjects. Interestingly, PyV miRNAs were found to be circulating in blood, urine, cerebrospinal fluid, and saliva samples from patients despite their PyV DNA status. Recently, the association between EVs and PyV viral particles was reported, demonstrating the ability of PyV viral particles to enter the cell without natural receptor-mediated entry and evade antibody-mediated neutralization or to be neutralized at a step different from that of the neutralization of naked whole viral particles. All these data point toward a potential role of the association between PyVs with EVs in viral persistence, suggesting that further work to define the implication of this interaction in viral reactivation is warranted.


Asunto(s)
Vesículas Extracelulares/virología , Infecciones por Polyomavirus/virología , Poliomavirus/fisiología , Infecciones Tumorales por Virus/virología , Animales , Humanos , MicroARNs/metabolismo , ARN Viral/metabolismo , Internalización del Virus
13.
PLoS Pathog ; 16(3): e1008403, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32203554

RESUMEN

The replication of small DNA viruses requires both host DNA replication and repair factors that are often recruited to subnuclear domains termed viral replication centers (VRCs). Aside from serving as a spatial focus for viral replication, little is known about these dynamic areas in the nucleus. We investigated the organization and function of VRCs during murine polyomavirus (MuPyV) infection using 3D structured illumination microscopy (3D-SIM). We localized MuPyV replication center components, such as the viral large T-antigen (LT) and the cellular replication protein A (RPA), to spatially distinct subdomains within VRCs. We found that viral DNA (vDNA) trafficked sequentially through these subdomains post-synthesis, suggesting their distinct functional roles in vDNA processing. Additionally, we observed disruption of VRC organization and vDNA trafficking during mutant MuPyV infections or inhibition of DNA synthesis. These results reveal a dynamic organization of VRC components that coordinates virus replication.


Asunto(s)
Núcleo Celular/virología , ADN Viral/metabolismo , Infecciones por Polyomavirus/metabolismo , Poliomavirus/fisiología , Replicación Viral/fisiología , Transporte Activo de Núcleo Celular/genética , Animales , Antígenos Virales de Tumores/genética , Antígenos Virales de Tumores/metabolismo , Línea Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , ADN Viral/genética , Ratones , Infecciones por Polyomavirus/genética , Proteína de Replicación A/genética , Proteína de Replicación A/metabolismo
14.
J Invest Dermatol ; 140(5): 976-985, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31759946

RESUMEN

Merkel cell carcinoma (MCC), an aggressive neuroendocrine carcinoma of the skin, is to date the only human cancer known to be frequently caused by a polyomavirus. However, it is a matter of debate which cells are targeted by the Merkel cell polyomavirus (MCPyV) to give rise to the phenotypically multifaceted MCC cells. To assess the lineage of origin of MCPyV-positive MCC, genetic analysis of a very rare tumor combining benign trichoblastoma and MCPyV-positive MCC was conducted by massive parallel sequencing. Although MCPyV was found to be integrated only in the MCC part, six somatic mutations were shared by both tumor components. The mutational overlap between the trichoblastoma and MCPyV-positive MCC parts of the combined tumor implies that MCPyV integration occurred in an epithelial tumor cell before MCC development. Therefore, our report demonstrates that MCPyV-positive MCC can derive from the epithelial lineage.


Asunto(s)
Carcinoma de Células de Merkel/diagnóstico , Folículo Piloso/patología , Neoplasias/diagnóstico , Infecciones por Polyomavirus/diagnóstico , Poliomavirus/fisiología , Neoplasias Cutáneas/diagnóstico , Piel/patología , Anciano , Carcinogénesis , Diferenciación Celular , Linaje de la Célula , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación/genética , Piel/virología , Infecciones Tumorales por Virus , Integración Viral
15.
Sci Rep ; 9(1): 13085, 2019 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-31511622

RESUMEN

New Jersey polyomavirus (NJPyV) was discovered in 2014 in a pancreatic transplant recipient's vascular endothelial cells. Here, in the recombinant baculovirus system, VP1 protein of NJPyV expressed in insect cells was processed. The protein self-assembled into virus-like particles (NJPyV-LPs) in a cell-type-dependent manner, and the particles were then released into the culture media. Spherical ~50-nm-dia. NJPyV-LPs of uniform size with morphology resembling that of the native particles of polyomaviruses were purified from the fraction at 1.33 g/cm3 in supernatants of VP1-expressing Sf9 cells. We investigated the antigenic properties of purified NJPyV-LPs and performed a VLP-based enzyme immunoassay to determine the age-specific prevalence of NJPyV infection in a general Japanese population aged 1-70 years. The overall seropositivity rate of anti-NJPyV antibodies was only 1.8%. This might be explained by the low circulation of NJPyV in Japan. This is the first report of a large-scale serological survey of NJPyV in Asia (n = 1,050).


Asunto(s)
Proteínas de la Cápside/química , Poliomavirus/fisiología , Agregado de Proteínas , Adolescente , Adulto , Anciano , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Proteínas de la Cápside/inmunología , Niño , Preescolar , Reacciones Cruzadas , Femenino , Humanos , Sueros Inmunes/inmunología , Lactante , Japón , Masculino , Persona de Mediana Edad , Poliomavirus/inmunología , Estudios Seroepidemiológicos , Células Sf9 , Spodoptera , Adulto Joven
16.
J Clin Virol ; 120: 6-11, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31505316

RESUMEN

BACKGROUND: While the pathogenicity of the two initially identified Human Polyomaviruses (HPyVs), BK Virus (BKPyV) and JC Virus (JCPyV) has been intensely studied, there is only limited data, on whether the occurrence of the recently discovered HPyVs correlates with high level BKPyV replication and progression towards Polyomavirus associated nephropathy (PVAN). METHODS: Therefore, we performed a comprehensive longitudinal genoprevalence analysis of 13 HPyVs using a novel multiplex assay including 400 serum and 388 urine samples obtained from 99 kidney transplant recipients (KTRs), grouped by quantitative BKPyV DNA loads and evidence of manifest BKPyV associated disease (histologically verified PVAN, high urinary decoy cell levels and concurrent decrease of renal function). RESULTS: In total, 3 different non-BKPyV/JCPyV HPyVs, Human Polyomavirus 9, Merkel Cell Polyomavirus (MCPyV) and Trichodysplasia Spinulosa associated Polyomavirus were detected in 11 blood and 21 urine samples from 21 patients. Although DNAemia of these viruses occurred more frequently during high level BKPyV DNAemia and PVAN, the increase of the detection frequency due to progression of BKPyV replication did not reach statistical significance for blood samples. The positive detection rate of MCPyV in urine, however, was significantly higher during BKPyV DNAemia in 19 KTRs of our cohort who suffered from histologically verified PVAN (p = 0.005). In one individual with PVAN, continuous long-term shedding of MCPyV in urine was observed. CONCLUSION: In our cohort the recently discovered HPyVs HPyV9, TSPyV and MCPyV emerged in blood from KTRs with variable kinetics, while detection of MCPyV DNAuria occurred more frequently during BKPyV DNAemia in patients with PVAN.


Asunto(s)
Virus BK/fisiología , Enfermedades Renales/virología , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/diagnóstico , Poliomavirus/fisiología , Adulto , Anciano , Virus BK/aislamiento & purificación , Estudios de Cohortes , ADN Viral/sangre , ADN Viral/orina , Femenino , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/orina , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Poliomavirus/aislamiento & purificación , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/orina , Infecciones por Polyomavirus/virología , Carga Viral , Replicación Viral , Esparcimiento de Virus , Adulto Joven
17.
Int J Mol Sci ; 20(16)2019 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-31408949

RESUMEN

Viruses are intracellular parasites that require a permissive host cell to express the viral genome and to produce new progeny virus particles. However, not all viral infections are productive and some viruses can induce carcinogenesis. Irrespective of the type of infection (productive or neoplastic), viruses hijack the host cell machinery to permit optimal viral replication or to transform the infected cell into a tumor cell. One mechanism viruses employ to reprogram the host cell is through interference with signaling pathways. Polyomaviruses are naked, double-stranded DNA viruses whose genome encodes the regulatory proteins large T-antigen and small t-antigen, and structural proteins that form the capsid. The large T-antigens and small t-antigens can interfere with several host signaling pathways. In this case, we review the interplay between the large T-antigens and small t-antigens with host signaling pathways and the biological consequences of these interactions.


Asunto(s)
Antígenos Virales de Tumores/inmunología , Infecciones por Polyomavirus/inmunología , Poliomavirus/inmunología , Transducción de Señal , Animales , Interacciones Huésped-Patógeno , Humanos , Poliomavirus/fisiología
18.
Adv Virus Res ; 104: 97-122, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31439154

RESUMEN

Viruses must navigate the complex endomembranous network of the host cell to cause infection. In the case of a non-enveloped virus that lacks a surrounding lipid bilayer, endocytic uptake from the plasma membrane is not sufficient to cause infection. Instead, the virus must travel within organelle membranes to reach a specific cellular destination that supports exposure or arrival of the virus to the cytosol. This is achieved by viral penetration across a host endomembrane, ultimately enabling entry of the virus into the nucleus to initiate infection. In this review, we discuss the entry mechanisms of three distinct non-enveloped DNA viruses-adenovirus (AdV), human papillomavirus (HPV), and polyomavirus (PyV)-highlighting how each exploit different intracellular transport machineries and membrane penetration apparatus associated with the endosome, Golgi, and endoplasmic reticulum (ER) membrane systems to infect a host cell. These processes not only illuminate a highly-coordinated interplay between non-enveloped viruses and their host, but may provide new strategies to combat non-enveloped virus-induced diseases.


Asunto(s)
Adenoviridae/fisiología , Interacciones Huésped-Patógeno , Papillomaviridae/fisiología , Poliomavirus/fisiología , Internalización del Virus , Endocitosis , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/virología , Endosomas/metabolismo , Endosomas/virología , Aparato de Golgi/metabolismo , Aparato de Golgi/virología , Humanos
19.
Philos Trans R Soc Lond B Biol Sci ; 374(1773): 20180301, 2019 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-30955497

RESUMEN

Human polyomaviruses show relatively little genetic polymorphism between isolates, indicating that these viruses are genetically stable between hosts. However, it has become increasingly clear that intra-host molecular evolution is a feature of some polyomavirus (PyV) infections in humans. Mutations inducing premature stop codons in the early region of the integrated Merkel cell PyV genome lead to the expression of a truncated form of the large tumour (LT) antigen that is critical for the transformation of Merkel cell carcinoma (MCC) cells. Non-coding control region (NCCR) rearrangements and point mutations in virion protein (VP) 1 have been described in both JCPyV and BKPyV infections. In the context of JCPyV infection, molecular evolution at both these loci allows the virus to replicate effectively in the central nervous system, thereby leading to the development of progressive multifocal leukoencephalopathy (PML). In BKPyV infection, NCCR rearrangements have been linked to higher rates of virus replication in the kidney, and are proposed to play a direct causal role in the development of PyV-associated nephropathy. In all three of these infections, therefore, intra-host viral evolution appears to be an essential component of the disease process. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.


Asunto(s)
Infecciones por Polyomavirus/virología , Poliomavirus/fisiología , Replicación Viral , Evolución Biológica , Humanos
20.
Bioorg Med Chem ; 27(9): 1795-1803, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30890396

RESUMEN

Opportunistic viruses are a major problem for immunosuppressed individuals, particularly following organ or stem cell transplantation. Current treatments are non-existent or suffer from problems such as high toxicity or development of resistant strains. We previously published that a trafficking inhibitor that targets a host protein greatly reduces the replication of human cytomegalovirus. This inhibitor was also shown to be moderately effective against polyomaviruses, another family of opportunistic viruses. We have developed a panel of analogues for this inhibitor and have shown that these analogues maintain their high efficacy against HCMV, while substantially lowering the concentration required to inhibit polyomavirus replication. By targeting a host protein these compounds are able to inhibit the replication of two very different viruses. These observations open up the possibility of pan-viral inhibitors for immunosuppressed individuals that are effective against multiple, diverse opportunistic viruses.


Asunto(s)
Antivirales/farmacología , Citomegalovirus/fisiología , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Ratones , Poliomavirus/fisiología , Quinazolinonas/química , Quinazolinonas/farmacología
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