The Experts below are selected from a list of 2778 Experts worldwide ranked by ideXlab platform
Petra Reinke - One of the best experts on this subject based on the ideXlab platform.
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BK Polyomavirus infection and nephropathy: the virus–immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:BK Polyomavirus (BKV) is a latent virus known to reactivate under immunosuppression BKV-associated nephropathy (BKVAN) is a complication of active BKV infection that mainly affects renal transplant recipients Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors for BKVAN No effective, specific therapy for BKVAN currently exists Frequent monitoring of BKV replication followed by judicious reduction or modification of immunosuppression (to improve antiviral immunity) is the current recommended approach for management of BKVAN An immune pathogenesis might dominate in patients with persistent BKV replication; reduction of immunosuppression as a therapeutic option for BKVAN should therefore be considered with caution in such patients Reactivation of latent BK Polyomavirus (BKV) infection is a major challenge in renal graft recipients and progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. This Review discusses the available data on the diagnosis and monitoring of BKV infection and BKVAN, describes the known risk factors for BKV-related disease, and reviews current approaches to treatment and prevention of both BKV infection and BKVAN. Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy the virus immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection is a major challenge in renal graft recipients and progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. This Review discusses the available data on the diagnosis and monitoring of BKV infection and BKVAN, describes the known risk factors for BKV-related disease, and reviews current approaches to treatment and prevention of both BKV infection and BKVAN. Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy: the virus–immune system interplay
Nature reviews. Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy the virus immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
Nina Babel - One of the best experts on this subject based on the ideXlab platform.
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BK Polyomavirus infection and nephropathy: the virus–immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:BK Polyomavirus (BKV) is a latent virus known to reactivate under immunosuppression BKV-associated nephropathy (BKVAN) is a complication of active BKV infection that mainly affects renal transplant recipients Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors for BKVAN No effective, specific therapy for BKVAN currently exists Frequent monitoring of BKV replication followed by judicious reduction or modification of immunosuppression (to improve antiviral immunity) is the current recommended approach for management of BKVAN An immune pathogenesis might dominate in patients with persistent BKV replication; reduction of immunosuppression as a therapeutic option for BKVAN should therefore be considered with caution in such patients Reactivation of latent BK Polyomavirus (BKV) infection is a major challenge in renal graft recipients and progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. This Review discusses the available data on the diagnosis and monitoring of BKV infection and BKVAN, describes the known risk factors for BKV-related disease, and reviews current approaches to treatment and prevention of both BKV infection and BKVAN. Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy the virus immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection is a major challenge in renal graft recipients and progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. This Review discusses the available data on the diagnosis and monitoring of BKV infection and BKVAN, describes the known risk factors for BKV-related disease, and reviews current approaches to treatment and prevention of both BKV infection and BKVAN. Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy: the virus–immune system interplay
Nature reviews. Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy the virus immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
Hans H Hirsch - One of the best experts on this subject based on the ideXlab platform.
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BK Polyomavirus-specific T Cells as a Diagnostic and Prognostic Marker for BK Polyomavirus Infections After Pediatric Kidney Transplantation.
Transplantation, 2020Co-Authors: Thurid Ahlenstiel-grunow, Hans H Hirsch, M. Sester, Urban Sester, Lars PapeAbstract:BACKGROUND After kidney transplantation, uncontrolled BK Polyomavirus (BKPyV) replication causes kidney graft failure through BKPyV-associated nephropathy (BKPyVAN), but markers predicting outcome are missing. BKPyV-specific T cells may serve as a predictive marker to identify patients at risk of persistent DNAemia and BKPyVAN. METHODS Out of a total of 114 pediatric kidney recipients transplanted between 2008 and 2018, 36 children with posttransplant BKPyV-DNAemia were identified. In a prospective noninterventional study, BKPyV-specific CD4 and CD8 T cells were measured in 32 of 36 viremic pediatric kidney recipients using intracellular cytokine staining and flow cytometry. The course of the BKPyV replication was monitored with regard to duration of BKPyV-DNAemia and need of therapeutic intervention and diagnosis of proven BKPyVAN. RESULTS Levels of BKPyV-specific T cells negatively correlated with subsequent duration of BKPyV-DNAemia. Patients with BKPyV-specific CD4 T cells ≥0.5 cells/µL and/or BKPyV-specific CD8 T cells ≥0.1 cells/µL had transient, self-limiting DNAemia (PPV 1.0, NPV 0.86). BKPyV-specific CD4 and CD8 T cells below these thresholds were found in children with persistent BKPyV-DNAemia and biopsy-proven BKPyVAN with need for therapeutic intervention. After reducing immunosuppressive therapy, levels of BKPyV-specific CD4 T cells increased while plasma BKPyV-DNAemia declined. CONCLUSIONS This study found that BKPyV-specific T cell levels may help to distinguish patients with transient, self-limiting BKPyV-DNAemia from those with persisting BKPyV-DNAemia and biopsy-proven BKPyVAN, who would benefit from individualized therapeutic interventions such as reduced immunosuppression. Thereby the risk for rejection because of unnecessary reduction of immunosuppression in case of self-limiting BKPyV-DNAemia can be minimized.
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simultaneous BK Polyomavirus BKpyv associated nephropathy and hemorrhagic cystitis after living donor kidney transplantation
Journal of Clinical Virology, 2016Co-Authors: Ilkka Helantera, Hans H Hirsch, Eeva Auvinen, Laura Mannonen, Marion Wernli, Fernanda Ortiz, Marko Lempinen, Anne Raisanensokolowski, I LautenschlagerAbstract:BK Polyomavirus (BKPyV) commonly reactivates after kidney transplantation, and can cause Polyomavirus-associated nephropathy (PyVAN), whereas after allogeneic stem cell transplantation the most frequent manifestation of BKPyV is Polyomavirus-associated hemorrhagic cystitis (PyVHC). Despite high-level BKPyV replication in both, the pathogenesis and manifestation of both BKPyV entities appears to differ substantially. We describe an unusual case of simultaneous PyVAN and PyVHC presenting with acute symptoms in a BKPyV-IgG positive recipient eight months after kidney transplantation from a haploidentical living donor, who was BKPyV-IgG negative. Symptoms of cystitis and viremia subsided rapidly after reduction of immunosuppression.
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BK Polyomavirus infection and renourinary tumorigenesis
American Journal of Transplantation, 2016Co-Authors: John C Papadimitriou, Hanssen C Rinaldo, Borislav A. Alexiev, Cinthia B Drachenberg, Parmjeet Randhawa, Hans H HirschAbstract:BK Polyomavirus (BKPyV) infection represents a major problem in transplantation, particularly for renal recipients developing Polyomavirus-associated nephropathy (PyVAN). The possibility that BKPyV may also be oncogenic is not routinely considered. Twenty high-grade renourinary tumors expressing Polyomavirus large T antigen in the entirety of the neoplasm in 19 cases, including the metastases in six, have been reported in transplant recipients with a history of PyVAN or evidence of BKPyV infection. Morphological and phenotypical features consistent with inactivation of the tumor suppressors pRB and p53 were found in the bladder tumors, suggesting a carcinogenesis mechanism involving the BKPyV large tumor oncoprotein/antigen. The pathogenesis of these tumors is unclear, but given the generally long interval between transplantation and tumor development, the risk for neoplasms after BKPyV infections may well be multifactorial. Other elements potentially implicated include exposure to additional exogenous carcinogens, further viral mutations, and cell genomic instability secondary to viral integration, as occurs with the Merkel cell PyV-associated carcinoma. The still scarce but increasingly reported association between longstanding PyVAN and renourinary neoplasms requires a concerted effort from the transplant community to better understand, diagnose, and treat the putative association between the BKPyV and these neoplasms.
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Human BK Polyomavirus Plasmid pBKV (34-2) (Dunlop) Contains Mutations Not Found in the Originally Published Sequences.
Genome announcements, 2015Co-Authors: Stian Henriksen, Hans H Hirsch, Christian Mittelholzer, Rainer Gosert, Christine Hanssen RinaldoAbstract:The plasmid pBKV (34-2) (ATCC 45025) contains the entire BK Polyomavirus Dunlop genome. Sequencing revealed 12 point mutations compared to the GenBank sequence, but only 4 point mutations compared to the published sequence. The origin of these differences is unknown, but may impact virological as well as diagnostic research and development.
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Diffuse gastrointestinal bleeding and BK Polyomavirus replication in a pediatric allogeneic haematopoietic stem cell transplant patient
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 2014Co-Authors: Markku Koskenvuo, Irmeli Lautenschlager, Piotr Kardas, Eeva Auvinen, Laura Mannonen, Pasi Huttunen, Mervi Taskinen, Kim Vettenranta, Hans H HirschAbstract:Patients undergoing haematopoietic stem cell transplantation (HSCT) are at high risk of severe gastrointestinal bleeding caused by infections, graft versus host disease, and disturbances in haemostasis. BK Polyomavirus (BKPyV) is known to cause hemorrhagic cystitis, but there is also evidence of BKV shedding in stool and its association with gastrointestinal disease. We report putative association of BKPyV replication with high plasma viral loads in a pediatric HSCT patient developing hemorrhagic cystitis and severe gastrointestinal bleeding necessitating intensive care. The observation was based on chart review and analysis of BKPyV DNA loads in plasma and urine as well as retrospective BKPyV-specific IgM and IgG measurements in weekly samples until three months post-transplant. The gastrointestinal bleeding was observed after a >100-fold increase in the plasma BKPyV loads and the start of hemorrhagic cystitis. The BKPyV-specific antibody response indicated past infection prior to transplantation, but increasing IgG titers were seen following BKPyV replication. The gastrointestinal biopsies were taken at a late stage of the episode and were no longer informative of BK Polyomavirus involvement. In conclusion, gastrointestinal complications with bleeding are a significant problem after allogeneic HSCT to which viral infections including BKPyV may contribute.
Michael J. Imperiale - One of the best experts on this subject based on the ideXlab platform.
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Control of Archetype BK Polyomavirus MicroRNA Expression.
Journal of virology, 2020Co-Authors: Wei Zou, Gau Shoua Vue, Benedetta Assetta, Heather Manza, Walter J. Atwood, Michael J. ImperialeAbstract:BK Polyomavirus (BKPyV) is a ubiquitous human pathogen, with over 80% of adults worldwide being persistently infected. BKPyV infection is usually asymptomatic in healthy people; however, it causes Polyomavirus-associated nephropathy in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. BKPyV has a circular, double-stranded DNA genome that is divided genetically into three parts: an early region, a late region, and a noncoding control region (NCCR). The NCCR contains the viral DNA replication origin and cis-acting elements regulating viral early and late gene expression. It was previously shown that a BKPyV microRNA (miRNA) expressed from the late strand regulates viral large-T-antigen expression and limits the replication capacity of archetype BKPyV. A major unanswered question in the field is how expression of the viral miRNA is regulated. Typically, miRNA is expressed from introns in cellular genes, but there is no intron readily apparent in BKPyV from which the miRNA could derive. Here, we provide evidence for primary RNA transcripts that circle the genome more than once and include the NCCR. We identified splice junctions resulting from splicing of primary transcripts circling the genome more than once, and Sanger sequencing of reverse transcription-PCR (RT-PCR) products indicates that there are viral transcripts that circle the genome up to four times. Our data suggest that the miRNA is expressed from an intron spliced out of these greater-than-genome-size primary transcripts.IMPORTANCE The BK Polyomavirus (BKPyV) miRNA plays an important role in regulating viral large-T-antigen expression and limiting the replication of archetype BKPyV, suggesting that the miRNA regulates BKPyV persistence. However, how miRNA expression is regulated is poorly understood. Here, we present evidence that the miRNA is expressed from an intron that is generated by RNA polymerase II transcribing the circular viral genome more than once. We identified splice junctions that could be generated only from primary transcripts that contain tandemly repeated copies of the viral genome. The results indicate another way in which viruses optimize expression of their genes using limited coding capacity.
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Control of archetype BK Polyomavirus miRNA expression
2020Co-Authors: Michael J. Imperiale, Wei Zou, Gau Shoua Vue, Benedetta Assetta, Heather Manza, Walter J. AtwoodAbstract:BK Polyomavirus (BKPyV) is a ubiquitous human pathogen, with over 80% of adults worldwide persistently infected. BKPyV infection is usually asymptomatic in healthy people; however, it causes Polyomavirus-associated nephropathy in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. BKPyV has a circular, double-stranded DNA genome that is divided genetically into three parts: an early region, a late region, and a non-coding control region (NCCR). The NCCR contains the viral DNA replication origin and cis-acting elements regulating viral early and late gene expression. It was previously shown that a BKPyV miRNA expressed from the late strand regulates viral large T antigen expression and limits the replication capacity of archetype BKPyV. A major unanswered question in the field is how expression of the viral miRNA is regulated. Typically, miRNA is expressed from introns in cellular genes but there is no intron readily apparent in the BKPyV from which the miRNA could derive. Here we provide evidence for primary RNA transcripts that circle the genome more than once and include the NCCR. We identified splice junctions resulting from splicing of primary transcripts circling the genome more than once, and Sanger sequencing of RT-PCR products indicates that there are viral transcripts that circle the genome up to four times. Our data suggest that the miRNA is expressed from the intron of these greater-than-genome size primary transcripts.
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Establishing Renal Proximal Tubule Epithelial-Derived Cell Lines Expressing Human Telomerase Reverse Transcriptase for Studying BK Polyomavirus.
Microbiology resource announcements, 2019Co-Authors: Linbo Zhao, Michael J. ImperialeAbstract:We previously established an infection model for BK Polyomavirus (BKPyV) in primary human renal proximal tubule epithelial (RPTE) cells. Use of these cells is limited by their inability to be passaged extensively. Here, we describe RPTE cells immortalized with human telomerase reverse transcriptase (hTERT), which can serve as a model system for acute or persistent BKPyV infection.
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Viral DNA Replication-Dependent DNA Damage Response Activation during BK Polyomavirus Infection
Journal of virology, 2015Co-Authors: Brandy Verhalen, Michael J. Imperiale, Joshua L. Justice, Mengxi JiangAbstract:ABSTRACT BK Polyomavirus (BKPyV) reactivation is associated with severe human disease in kidney and bone marrow transplant patients. The interplay between viral and host factors that regulates the productive infection process remains poorly understood. We have previously reported that the cellular DNA damage response (DDR) is activated upon lytic BKPyV infection and that its activation is required for optimal viral replication in primary kidney epithelial cells. In this report, we set out to determine what viral components are responsible for activating the two major phosphatidylinositol 3-kinase-like kinases (PI3KKs) involved in the DDR: ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3-related (ATR) kinase. Using a combination of UV treatment, lentivirus transduction, and mutant virus infection experiments, our results demonstrate that neither the input virus nor the expression of large T antigen (TAg) alone is sufficient to trigger the activation of ATM or ATR in our primary culture model. Instead, our data suggest that the activation of both the ATM- and ATR-mediated DDR pathways is linked to viral DNA replication. Intriguingly, a TAg mutant virus that is unable to activate the DDR causes substantial host DNA damage. Our study provides insight into how DDRs are activated by Polyomaviruses in primary cells with intact cell cycle checkpoints and how the activation might be linked to the maintenance of host genome stability. IMPORTANCE Polyomaviruses are opportunistic pathogens that are associated with several human diseases under immunosuppressed conditions. BK Polyomavirus (BKPyV) affects mostly kidney and bone marrow transplant patients. The detailed replication mechanism of these viruses remains to be determined. We have previously reported that BKPyV activates the host DNA damage response (DDR), a response normally used by the host cell to combat genotoxic stress, to aid its own replication. In this study, we identified that the trigger for DDR activation is viral replication. Furthermore, we show that the virus is able to cause host DNA damage in the absence of viral replication and DDR activation. These results suggest an intricate relationship between viral replication, DDR activation, and host genome instability.
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mirna regulation of BK Polyomavirus replication during early infection
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Nicole M. Broekema, Michael J. ImperialeAbstract:Viral microRNAs (miRNAs) play an important role during infection by posttranscriptionally regulating both host and viral gene expression. However, the function of many viral miRNAs remains poorly understood. In this study, we investigated the role of the BK Polyomavirus (BKPyV) miRNA in regulating virus replication. The function of the Polyomavirus miRNA was investigated in archetype BKPyV, which is the transmissible form of the virus and thought to establish a persistent infection in the host urinary tract. In agreement with previous studies, we show that the BKPyV miRNA targets early mRNAs. Importantly, we show that the miRNA plays a significant role in limiting archetype BKPyV replication in a natural host cell model of infection. This regulation is accomplished through the balance of regulatory elements located within the noncoding control region that control early gene expression and miRNA expression before genome replication. We therefore provide evidence for a unique function of the Polyomavirus miRNA that may have important implications for the mechanism of viral persistence.
Hans-dieter Volk - One of the best experts on this subject based on the ideXlab platform.
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BK Polyomavirus infection and nephropathy: the virus–immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:BK Polyomavirus (BKV) is a latent virus known to reactivate under immunosuppression BKV-associated nephropathy (BKVAN) is a complication of active BKV infection that mainly affects renal transplant recipients Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors for BKVAN No effective, specific therapy for BKVAN currently exists Frequent monitoring of BKV replication followed by judicious reduction or modification of immunosuppression (to improve antiviral immunity) is the current recommended approach for management of BKVAN An immune pathogenesis might dominate in patients with persistent BKV replication; reduction of immunosuppression as a therapeutic option for BKVAN should therefore be considered with caution in such patients Reactivation of latent BK Polyomavirus (BKV) infection is a major challenge in renal graft recipients and progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. This Review discusses the available data on the diagnosis and monitoring of BKV infection and BKVAN, describes the known risk factors for BKV-related disease, and reviews current approaches to treatment and prevention of both BKV infection and BKVAN. Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy the virus immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection is a major challenge in renal graft recipients and progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. This Review discusses the available data on the diagnosis and monitoring of BKV infection and BKVAN, describes the known risk factors for BKV-related disease, and reviews current approaches to treatment and prevention of both BKV infection and BKVAN. Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy: the virus–immune system interplay
Nature reviews. Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.
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BK Polyomavirus infection and nephropathy the virus immune system interplay
Nature Reviews Nephrology, 2011Co-Authors: Nina Babel, Hans-dieter Volk, Petra ReinkeAbstract:Reactivation of latent BK Polyomavirus (BKV) infection continues to be a major challenge in renal graft recipients. Progression of BKV infection to BKV-associated nephropathy (BKVAN) leads to graft loss in up to 60% of affected patients. Interestingly, although >80% of healthy adults are seropositive for BKV, BKVAN occurs almost exclusively in transplanted kidneys, which raises questions about its underlying pathogenetic mechanisms. Intragraft inflammation and an insufficient antiviral immune response seem to be the most important risk factors. Early studies revealed an association between the rate of recovery of BKV-specific cellular immunity (which shows high interindividual variation) and BK viral clearance, which determines the clinical course of BKV infection. In patients with prompt recovery of BKV-specific T cells, BKV infection can be controlled at the early reactivation stage and does not progress to BKVAN. By contrast, in patients with persistent BKV reactivation caused by insufficient BKV-specific immunity, continued viral replication and inflammation ultimately lead to graft injury and/or BKVAN. As the chronic course of BKV infection can be prevented in most patients by prompt restoration of BKV-specific immunity, frequent monitoring of BK viral load and targeted, timely modification or reduction of immunosuppression is strongly recommended for affected patients.