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Journal of Neuroimmune Pharmacology :... Dec 2019With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased... (Review)
Review
With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased incidence of Progressive Multifocal Leukoencephalopathy (PML). Currently, there are no pharmaceutical agents targeting JCV infection for the treatment and the prevention of viral reactivation leading to the development of PML. As JCV primarily reactivates in immunocompromised patients, it is proposed that the immune system (mainly the cellular-immunity component) plays a key role in the regulation of JCV to prevent productive infection and PML development. However, the exact mechanism of JCV immune regulation and reactivation is not well understood. Likewise, the impact of host factors on JCV regulation and reactivation is another understudied area. Here we discuss the current literature on host factor-mediated and immune factor-mediated regulation of JCV gene expression with the purpose of developing a model of the factors that are bypassed during JCV reactivation, and thus are potential targets for the development of therapeutic interventions to suppress PML initiation. Graphical Abstract.
Topics: Animals; Host Microbial Interactions; Humans; Immunocompromised Host; Immunotherapy; JC Virus; Leukoencephalopathy, Progressive Multifocal; Virus Activation
PubMed: 31452013
DOI: 10.1007/s11481-019-09877-8 -
Frontiers in Immunology 2014Progressive multifocal leukoencephalopathy (PML) is a severely debilitating and often fatal demyelinating disease of the central nervous system (CNS) in immunosuppressed... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a severely debilitating and often fatal demyelinating disease of the central nervous system (CNS) in immunosuppressed individuals caused by JC polyomavirus (JCV), a ubiquitous human pathogen. Demyelination results from lytically infected oligodendrocytes, whose clearance is impaired in the setting of depressed JCV-specific T cell-mediated CNS surveillance. Although mutations in the viral capsid and genomic rearrangements in the viral non-coding region appear to set the stage for PML in the immunosuppressed population, mechanisms of demyelination and CNS antiviral immunity are poorly understood in large part due to absence of a tractable animal model that mimics PML neuropathology in humans. Early studies using mouse polyomavirus (MPyV) in T cell-deficient mice demonstrated productive viral replication in the CNS and demyelination; however, these findings were confounded by spinal cord compression by virus-induced vertebral bone tumors. Here, we review current literature regarding animal models of PML, focusing on current trends in antiviral T cell immunity in non-lymphoid organs, including the CNS. Advances in our understanding of polyomavirus lifecycles, viral and host determinants of persistent infection, and T cell-mediated immunity to viral infections in the CNS warrant revisiting polyomavirus CNS infection in the mouse as a bona fide animal model for JCV-PML.
PubMed: 25601860
DOI: 10.3389/fimmu.2014.00646 -
The Journal of Infectious Diseases Oct 2021Human polyomaviruses can reactivate in transplant patients, causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic, rash or...
BACKGROUND
Human polyomaviruses can reactivate in transplant patients, causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic, rash or trichodysplasia spinulosa. Sirolimus and related mechanistic target of rapamycin (mTOR) inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression.
METHODS
In vitro expression and turnover of large T (LT) proteins from BK virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication, and whole virus immunofluorescence assays.
RESULTS
mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and increase in virus replication for JCV, MCV, TSV, and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV, and HPyV7.
CONCLUSIONS
mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immunosuppression.
Topics: BK Virus; DNA Replication; DNA, Viral; Humans; JC Virus; MTOR Inhibitors; Merkel cell polyomavirus; Polyomavirus; Polyomavirus Infections; S-Phase Kinase-Associated Proteins; Sirolimus; TOR Serine-Threonine Kinases; Tacrolimus; Virus Replication
PubMed: 32060513
DOI: 10.1093/infdis/jiaa071 -
Frontiers in Microbiology 2017Infectious agents are common companions of humans and since ancient times they follow human migration on their search for a better place to live. The study of... (Review)
Review
Infectious agents are common companions of humans and since ancient times they follow human migration on their search for a better place to live. The study of paleomicrobiology was significantly improved in its accuracy of measurement with the constant development of better methods to detect and analyze nucleic acids. Human tissues are constantly used to trace ancient infections and the association of anthropological evidences are important to confirm the microbiological information. Infectious agents which establish human persistent infections are particularly useful to trace human migrations. In the present article, the evidence of infection by viral agents such as human T-lymphotropic virus 1, human T-lymphotropic virus 2, human herpes virus-8, JC virus, and a bacterium, , was described using different methodologies for their detection. Their presence was further used as biomarkers associated with anthropological and other relevant information to trace human migration into the Amazon region of Brazil. The approach also evidenced their microbiological origin, emergence, evolution, and spreading. The information obtained confirms much of the archeological information available tracing ancient and more recent human migration into this particular geographical region. In this article, the paleomicrobiological information on the subject was summarized and reviewed.
PubMed: 28912770
DOI: 10.3389/fmicb.2017.01663 -
Expert Opinion on Drug Safety Aug 2017Natalizumab is a humanized monoclonal antibody highly effective in relapsing-remitting multiple sclerosis (MS). Important concerns about its safety have been pointed out... (Review)
Review
Natalizumab is a humanized monoclonal antibody highly effective in relapsing-remitting multiple sclerosis (MS). Important concerns about its safety have been pointed out mainly because of the risk of progressive multifocal leukoencephalopathy (PML), caused by the opportunistic John-Cunningham virus (JCV). Areas covered: This review analyzes all the safety aspects related to the use and safety of natalizumab in MS patients. Other than PML, post-marketing, safety red-flags have been reported, as liver or haematological serious adverse events. Pregnancy evidences will be pointed out. The risk of PML depends on: concomitant or previous immunosuppression, exposure duration, anti-JCV antibody level. In natalizumab-related PML the average survival is 77%; prognostic features and information for the earliest identification of PML have been identified to maximally reduce its incidence, mortality and morbidity. Expert opinion: Natalizumab is a highly effective drug for MS patients but its safety issues represent a relevant limitation and impose strict clinical surveillance of treated patients. Some post-marketing safety red-flags have been pointed out, with higher attention to severe liver failures and limphoma cases. If PML and its consequences are considered the most relevant issues, a continuous surveillance must be maintained also regarding other possible SAEs like liver diseases and malignancies.
Topics: Animals; Humans; Immunologic Factors; JC Virus; Leukoencephalopathy, Progressive Multifocal; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Opportunistic Infections; Prognosis; Risk; Survival Rate
PubMed: 28641055
DOI: 10.1080/14740338.2017.1346082 -
Virology Journal Aug 2022The John Cunningham virus (JCV) is the established etiological agent of the polyomavirus-associated nephropathy among renal transplant recipients. In the present study,...
BACKGROUND AND AIMS
The John Cunningham virus (JCV) is the established etiological agent of the polyomavirus-associated nephropathy among renal transplant recipients. In the present study, we aimed to determine the probable predictive factors leading to JCV replication in renal transplant patients.
MATERIAL AND METHODS
Urine and plasma samples were collected from a total of 120 consecutive renal-transplanted patients without preliminary screening from Jan 2018 to Mar 2019. After DNA extraction, the simultaneous detection and quantification of JCV and BK polyomavirus (BKV) were conducted using a Real-time quantitative PCR method. Moreover, statistical analyses were performed using the statistical software packages, SPSS version 21.
RESULTS
The prevalence of JCV viruria and viremia among renal transplant recipients were 26 (21.67%) and 20 (16.67%), respectively. A significant association was observed between the JCV and two risk factors, diabetes mellitus (P = 0.002) and renal stones (P = 0.015). The prevalence of JCV viremia among recipients who were grafted near time to sampling was significantly higher (P = 0.02). There was a statistically significant coexistence between BK and JC viruses among our patients (P = 0.029). The frequency of JCV viruria in males was reported almost three times more than in females (P = 0.005). The JCV shedding in urine was significantly associated with the tropical steroids like prednisolone acetate, which have been the standard regimen (P = 0.039). Multivariable analysis revealed duration of post-transplantation (OR, 0.89; P = 0.038), diabetes mellitus (OR, 1.85; P = 0.034), and renal stone (OR 1.10; P = 0.04) as independent risk factors associated with JCV viremia post-renal transplantation.
CONCLUSION
It seems that the discovery of potential risk factors, including immunological and non-immunological elements, may offer a possible preventive or therapeutic approach in the JCV disease episodes. The results of this study may also help clarify the probable clinical risk factors involving in progressive multifocal leukoencephalopathy development.
Topics: BK Virus; DNA, Viral; Female; Humans; JC Virus; Kidney Diseases; Kidney Transplantation; Male; Polyomavirus Infections; Transplant Recipients; Tumor Virus Infections; Viremia
PubMed: 35941650
DOI: 10.1186/s12985-022-01843-w -
Virology Jan 2021JC virus encodes an important regulatory protein, known as Agnoprotein (Agno). We have recently reported Agno's first protein-interactome with its cellular partners...
JC virus encodes an important regulatory protein, known as Agnoprotein (Agno). We have recently reported Agno's first protein-interactome with its cellular partners revealing that it targets various cellular networks and organelles, including mitochondria. Here, we report further characterization of the functional consequences of its mitochondrial targeting and demonstrated its co-localization with the mitochondrial networks and with the mitochondrial outer membrane. The mitochondrial targeting sequence (MTS) of Agno and its dimerization domain together play major roles in this targeting. Data also showed alterations in various mitochondrial functions in Agno-positive cells; including a significant reduction in mitochondrial membrane potential, respiration rates and ATP production. In contrast, a substantial increase in ROS production and Ca uptake by the mitochondria were also observed. Finally, findings also revealed a significant decrease in viral replication when Agno MTS was deleted, highlighting a role for MTS in the function of Agno during the viral life cycle.
Topics: Adenosine Triphosphate; Calcium; Cell Respiration; Dimerization; Humans; JC Virus; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membranes; Reactive Oxygen Species; Viral Regulatory and Accessory Proteins; Viroporin Proteins; Virus Replication
PubMed: 33278736
DOI: 10.1016/j.virol.2020.11.004 -
Microbiology and Immunology Nov 2022There are a limited number of studies regarding the involvement of viruses in the development and pathogenesis of renal cell carcinoma (RCC). In this study, we aimed to...
Human herpesvirus 6A and 6B and polyomavirus JC and BK infections in renal cell carcinoma and their relationship with p53, p16INK4a, Ki-67, and nuclear factor-kappa B expression.
There are a limited number of studies regarding the involvement of viruses in the development and pathogenesis of renal cell carcinoma (RCC). In this study, we aimed to discover whether human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) and human polyomavirus JC (JCV) and BK (BKV) are associated with RCC and the expression of p53, p16INK4a, Ki-67, and nuclear factor-κB (NF-κB) in patients with RCC. A total of 122 histologically confirmed RCC tissue specimens and 96 specimens of their corresponding peritumoral tissues were included in this prospective study. Nested PCR was performed to amplify viral DNA sequences. Restriction endonuclease analysis was carried out to discriminate between HHV-6A and HHV-6B. p53, p16INK4a, Ki-67, and NF-κB immunostaining data of the studied tissue specimens were available from our previous study. Statistical analysis was performed to demonstrate the potential associations. HHV-6B and JCV were detected in 10.7% and 13.9% of patients with RCC, respectively. We did not detect HHV-6A and BKV in any of RCC tissue specimens. Moreover, no association was found between either of these viruses and RCC. Our study revealed a significant association between HHV-6B and p53 overexpression. No other associations were found between cellular biomarkers p53, p16INK4a, Ki-67, and NF-κB and the studied viruses. The data of this study, though very limited, disprove the involvement of HHV-6A, HHV-6B, BKV, and JCV in the initiation or progression of RCC.
Topics: Humans; Carcinoma, Renal Cell; DNA, Viral; Herpesvirus 6, Human; JC Virus; Ki-67 Antigen; Kidney Neoplasms; NF-kappa B; Prospective Studies; Tumor Suppressor Protein p53
PubMed: 36073532
DOI: 10.1111/1348-0421.13026 -
Journal of Virology Jun 2018JC polyomavirus was discovered in 1971, and its name was derived from the initials of the individual from whose brain tissue it was isolated. While most scientists refer...
JC polyomavirus was discovered in 1971, and its name was derived from the initials of the individual from whose brain tissue it was isolated. While most scientists refer to the virus properly, i.e., calling it JCV or JCPyV, there is a small but palpable number of scientists who refer to the virus by the full name of the patient from whom it was isolated. This practice should stop.
Topics: Biomedical Research; Brain; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 29643238
DOI: 10.1128/JVI.00561-18 -
Revista Da Associacao Medica Brasileira... Nov 2017Few studies directly compare urinary cytology with molecular methods for detecting BK and JC polyomaviruses. Reactivation of BKV infection is the main risk factor for...
Few studies directly compare urinary cytology with molecular methods for detecting BK and JC polyomaviruses. Reactivation of BKV infection is the main risk factor for the development of nephropathy in immunocompromised individuals. The limitation of the cytological method can be attributed to the stage where the infected cell does not have specific and sufficient morphological characteristics for a conclusive diagnosis and can be easily interpreted as degenerative alteration. Moreover, morphologically, it is not possible to differentiate the two types of viruses. Polymerase chain reaction (PCR), not only is a sensitive method, but also allows differentiation of viral types without quantification, and therefore is not indicative of nephropathy. According to the American Society of Nephrology, real-time PCR would be the gold standard to indicate nephropathy because it allows quantifying the number of viral copies.
Topics: BK Virus; DNA, Viral; Humans; JC Virus; Polymerase Chain Reaction; Polyomavirus; Polyomavirus Infections
PubMed: 29451655
DOI: 10.1590/1806-9282.63.11.943