Levofloxacin for BK Virus Prophylaxis Following Kidney Transplantation

Knoll, Greg; Humar, Atul; Fergusson, Dean; Johnston, Olwyn; House, Andrew A.; Kim, S Joseph; Ramsay, Tim; Chassé, Michaël; Pang, Xiaoli; Zaltzman, Jeff; Cockfield, Sandra M.; Cantarovich, Marcelo; Karpinski, Martin; LeBel, Louise; Gill, John S.

doi:10.1001/jama.2014.14721

Cited by 109 publications

(92 citation statements)

References 29 publications

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“…Further studies on the structure of TAg will be required to clarify the role of the mutation in the structure, expression, and function of this protein. There are no drugs that can reduce polyomavirus replication efficiently in vivo (42)(43)(44). Since the inhibition of TAg function results in impairing virus replication (45)(46)(47), the single amino acid V392 might be a target for the inhibition of JCV replication.…”

Section: Discussionmentioning

confidence: 99%

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Takahashi

Sekizuka

Fukumoto

et al. 2017

J Virol

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JC virus (JCV) is a DNA virus causing progressive multifocal leukoencephalopathy (PML) in immunodeficient patients. In the present study, 22 genetic quasispecies with more than 1.5% variant frequency were detected in JCV genomes from six clinical samples of PML by next-generation sequencing. A mutation from A to C at nucleotide (nt) 3495 in JCV Mad1 resulting in a V-to-G amino acid substitution at amino acid (aa) position 392 of the large T antigen (TAg) was identified in all six cases of PML at 3% to 19% variant frequencies. Transfection of JCV Mad1 DNA possessing the V392G substitution in TAg into IMR-32 and human embryonic kidney 293 (HEK293) cells resulted in dramatically decreased production of JCV-encoded proteins. The virus DNA copy number was also reduced in supernatants of the mutant virus-transfected cells. Transfection of the IMR-32 and HEK293 cells with a virus genome containing a revertant mutation recovered viral production and protein expression. Cotransfection with equal amounts of wild-type genome and mutated JCV genome did not reduce the expression of viral proteins or viral replication, suggesting that the mutation did not have any dominantnegative function. Finally, immunohistochemistry demonstrated that TAg was expressed in all six pathological samples in which the quasispecies were detected. In conclusion, the V392G amino acid substitution in TAg identified frequently in PML lesions has a function in suppressing JCV replication, but the frequency of the mutation was restricted and its role in PML lesions was limited.IMPORTANCE DNA viruses generally have lower mutation frequency than RNA viruses, and the detection of quasispecies in JCV has rarely been reported. In the present study, a next-generation sequencer identified a JCV quasispecies with an amino acid substitution in the T antigen in patients with PML. In vitro studies showed that the mutation strongly repressed the expression of JC viral proteins and reduced the viral replication. However, because the frequency of the mutation was low in each case, the total expression of virus proteins was sustained in vivo. Thus, JC virus replicates in PML lesions in the presence of a mutant virus which is able to repress virus replication.

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Section: Discussionmentioning

confidence: 99%

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Takahashi

Sekizuka

Fukumoto

et al. 2017

J Virol

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“…PyVAN and PyVHC have a significant impact on morbidity and graft and patient survival 11, 12, 13, 14, 15, 16, 17, 18. Despite considerable virologic research 19, 20, 21, 22, 23, randomized clinical studies either are lacking or failed to demonstrate effective antiviral therapies 24. In kidney transplantation (KT), high‐level BKPyV viruria and viremia have been identified as markers of progression to PyVAN 25, thus current management strategies recommend screening KTRs for viremia followed by reducing immunosuppression 26, 27, 28.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

Cioni

Leboeuf

Comoli

et al. 2016

American Journal of Transplantation

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Uncontrolled BK polyomavirus (BKPyV) replication in kidney transplant recipients (KTRs) causes polyomavirus‐associated nephropathy and allograft loss. Reducing immunosuppression is associated with clearing viremia and nephropathy and increasing BKPyV‐specific T cell responses in most patients; however, current immunoassays have limited sensitivity, target mostly CD4+ T cells, and largely fail to predict onset and clearance of BKPyV replication. To characterize BKPyV‐specific CD8+ T cells, bioinformatics were used to predict 9mer epitopes in the early viral gene region (EVGR) presented by 14 common HLAs in Europe and North America. Thirty‐nine EVGR epitopes were experimentally confirmed by interferon‐γ enzyme‐linked immunospot assays in at least 30% of BKPyV IgG–seropositive healthy participants. Most 9mers clustered in domains, and some were presented by more than one HLA class I, as typically seen for immunodominant epitopes. Specific T cell binding using MHC class I streptamers was demonstrated for 21 of 39 (54%) epitopes. In a prospective cohort of 118 pediatric KTRs, 19 patients protected or recovering from BKPyV viremia were experimentally tested, and 13 epitopes were validated. Single HLA mismatches were not associated with viremia, suggesting that failing immune control likely involves multiple factors including maintenance immunosuppression. Combining BKPyV load and T cell assays using immunodominant epitopes may help in evaluating risk and reducing immunosuppression and may lead to safe adoptive T cell transfer.

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“…Usually, six doses are recommended 68 . It is stated that the first three doses can be administered safely without affecting lymphocyte but remaining dosages to be planned according to white cell and platelet count 69 .…”

Section: And54mentioning

confidence: 99%

The Anti-thymocyte Globulin use makes kidney transplantation journey smooth

Mahmood¹,

Ahmed²,

Aqeel³

et al. 2018

Int. j. endorsing health sci. res.

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Background: The most common immunosuppressant, Anti-thymocyte Globulin (ATGs) has been widely used by clinicians for the treatment and prevention of rejection at the time of organ transplant. Transplantation is the best option for the people with renal failure at end stage, requiring replacement of renal therapy. This is a promising treatment option with significant benefits in terms of mortality and morbidity. ATG prevents organ rejection by inhibition of activated T-cells and other immune and nonimmune cells. The aim of the study was to compare different induction regimens with ATG for the survival of smooth kidney transplantation. Methodology: Studies of the last 20 years, focusing on kidney transplantation and the efficacy of antithymocyte use for kidney transplantation were reviewed for the study literature. The keywords used were Kidney Transplantation, Induction agents, ATG, Allograft, Immunosuppressant Agents. Results: Literature suggested that the most important problem with transplantation is the protection of the allograft from activated immunological forces, which begin to react early in the period after transplantation and cause significant damage with serious short-term and long-term consequences. This process is called rejection, which is usually classified as cell-mediated and antibody-mediated rejection. The phenomenon mediated by cells causes concern, as it is the cause of future failures and damage to the allograft. To combat these phenomena with different results, various strategies were adopted. Among these therapies, ATG has recognized the exceptional importance of preventing cellular mediated rejection, allowing allotransplants to function smoothly with the greatest possible long-term benefits. Conclusion: It can be concluded on the basis of previous studies that ATG as an induction agent, is more efficient in reducing the rejection rate in the renal transplantation as compared with other agents.

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Levofloxacin for BK Virus Prophylaxis Following Kidney Transplantation

Abstract: clinicaltrials.gov Identifier: NCT01353339.

Cited by 109 publications

References 29 publications

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

The Anti-thymocyte Globulin use makes kidney transplantation journey smooth

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