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Viruses Nov 2022The organization and dynamics of plasma membrane receptors are a critical link in virus-receptor interactions, which finetune signaling efficiency and determine cellular...
The organization and dynamics of plasma membrane receptors are a critical link in virus-receptor interactions, which finetune signaling efficiency and determine cellular responses during infection. Characterizing the mechanisms responsible for the active rearrangement and clustering of receptors may aid in developing novel strategies for the therapeutic treatment of viruses. Virus-receptor interactions are poorly understood at the nanoscale, yet they present an attractive target for the design of drugs and for the illumination of viral infection and pathogenesis. This study utilizes super-resolution microscopy and related techniques, which surpass traditional microscopy resolution limitations, to provide both a spatial and temporal assessment of the interactions of human JC polyomavirus (JCPyV) with 5-hydroxytrypamine 2 receptors (5-HTRs) subtypes during viral entry. JCPyV causes asymptomatic kidney infection in the majority of the population and can cause fatal brain disease, and progressive multifocal leukoencephalopathy (PML), in immunocompromised individuals. Using Fluorescence Photoactivation Localization Microscopy (FPALM), the colocalization of JCPyV with 5-HT receptor subtypes (5-HT, 5-HT, and 5-HT) during viral attachment and viral entry was analyzed. JCPyV was found to significantly enhance the clustering of 5-HT receptors during entry. Cluster analysis of infected cells reveals changes in 5-HT receptor cluster attributes, and radial distribution function (RDF) analyses suggest a significant increase in the aggregation of JCPyV particles colocalized with 5-HT receptor clusters in JCPyV-infected samples. These findings provide novel insights into receptor patterning during viral entry and highlight improved technologies for the future development of therapies for JCPyV infection as well as therapies for diseases involving 5-HT receptors.
Topics: Humans; JC Virus; Serotonin; Leukoencephalopathy, Progressive Multifocal; Polyomavirus Infections; Virus Attachment
PubMed: 36560603
DOI: 10.3390/v14122597 -
Revista Da Sociedade Brasileira de... 2020Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of JC virus (JCV).
INTRODUCTION
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of JC virus (JCV).
METHODS
We described the profile of laboratory-confirmed PML cases among AIDS patients.
RESULTS
A total of 43 HIV patients with clinical conditions compatible with PML were obtained; 5 cases were confirmed by JCV testing. The main clinical finding was mental confusion. Median CD4 count was 54 cells/mm³.
CONCLUSIONS
Three of the five confirmed PML cases died; the time between diagnosis and death was 2, 5, and 6 months. It is important to consider JCV infection as a differential diagnosis.
Topics: Acquired Immunodeficiency Syndrome; CD4 Lymphocyte Count; DNA, Viral; HIV Infections; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 33338109
DOI: 10.1590/0037-8682-0252-2020 -
Viruses May 2022JC polyomavirus (JCPyV) is a small non-enveloped virus that establishes lifelong, persistent infection in most of the adult population. Immune-competent patients are... (Review)
Review
JC polyomavirus (JCPyV) is a small non-enveloped virus that establishes lifelong, persistent infection in most of the adult population. Immune-competent patients are generally asymptomatic, but immune-compromised and immune-suppressed patients are at risk for the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Studies with purified JCPyV found it undergoes receptor-dependent infectious entry requiring both lactoseries tetrasaccharide C (LSTc) attachment and 5-hydroxytryptamine type 2 entry receptors. Subsequent work discovered the major targets of JCPyV infection in the central nervous system (oligodendrocytes and astrocytes) do not express the required attachment receptor at detectable levels, virus could not bind these cells in tissue sections, and viral quasi-species harboring recurrent mutations in the binding pocket for attachment. While several research groups found evidence JCPyV can use novel receptors for infection, it was also discovered that extracellular vesicles (EVs) can mediate receptor independent JCPyV infection. Recent work also found JCPyV associated EVs include both exosomes and secretory autophagosomes. EVs effectively present a means of immune evasion and increased tissue tropism that complicates viral studies and anti-viral therapeutics. This review focuses on JCPyV infection mechanisms and EV associated and outlines key areas of study necessary to understand the interplay between virus and extracellular vesicles.
Topics: Astrocytes; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Neurodegenerative Diseases; Polyomavirus Infections
PubMed: 35746603
DOI: 10.3390/v14061130 -
Journal of Cellular Physiology Dec 2015Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the CNS caused by the human polyomavirus JC (JCV). JCV replication occurs only in... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the CNS caused by the human polyomavirus JC (JCV). JCV replication occurs only in human cells and investigation of PML has been severely hampered by the lack of an animal model. The common feature of PML is impairment of the immune system. The key to understanding PML is working out the complex mechanisms that underlie viral entry and replication within the CNS and the immunosurveillance that suppresses the virus or allows it to reactivate. Early models involved the simple inoculation of JCV into animals such as monkeys, hamsters, and mice. More recently, mouse models transgenic for the gene encoding the JCV early protein, T-antigen, a protein thought to be involved in the disruption of myelin seen in PML, have been employed. These animal models resulted in tumorigenesis rather than demyelination. Another approach is to use animal polyomaviruses that are closely related to JCV but able to replicate in the animal such as mouse polyomavirus and SV40. More recently, novel models have been developed that involve the engraftment of human cells into the animal. Here, we review progress that has been made to establish an animal model for PML, the advances and limitations of different models and weigh future prospects.
Topics: Animals; Animals, Genetically Modified; Brain; Disease Models, Animal; Genetic Predisposition to Disease; Host-Pathogen Interactions; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Myelin Sheath; Phenotype; Species Specificity; Virus Replication
PubMed: 26041694
DOI: 10.1002/jcp.25047 -
Current Opinion in Nephrology and... Jan 2019The presence of viruses in urine (urine virome) typically reflects infection in the kidneys and urinary tract. The urinary virome is associated with HIV-associated... (Review)
Review
PURPOSE OF REVIEW
The presence of viruses in urine (urine virome) typically reflects infection in the kidneys and urinary tract. The urinary virome is associated with HIV-associated nephropathy and chronic glomerulosclerosis. There are many associations of this microbiome with human diseases that remain to be described. This manuscript reviews emerging data on relationships between kidney disease and urinary tract infection/colonization with JC polyomavirus (JCPyV).
RECENT FINDINGS
Approximately 30% of the adult population sheds JCPyV in the urine. Further, urinary tract infection with one polyomavirus strain appears to inhibit secondary infections. The presence of urinary JCPyV and BK polyomavirus (BKPyV) replication were measured with polymerase chain reaction in African Americans to assess relationships with apolipoprotein L1 gene (APOL1)-associated nephropathy. Urinary JCPyV was associated with paradoxically lower rates of nephropathy in those with APOL1 high-risk genotypes. Subsequent studies revealed African Americans with JCPyV viruria had lower rates of nondiabetic nephropathy independent from APOL1.
SUMMARY
Urinary tract JCPyV replication is common and associates with lower rates of nephropathy. This relationship is observed in diverse settings. Results support a host immune system that fails to eradicate nonnephropathic viruses and is also less likely to manifest renal parenchymal inflammation resulting in glomerulosclerosis.
Topics: Apolipoprotein L1; Humans; JC Virus; Kidney Diseases; Urinary Tract Infections; Urine; Virus Replication
PubMed: 30320619
DOI: 10.1097/MNH.0000000000000464 -
Brain : a Journal of Neurology Apr 2022Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.
Topics: Brain; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Prospective Studies
PubMed: 34791056
DOI: 10.1093/brain/awab419 -
The FEBS Journal Oct 2022JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in immune-compromised individuals. The most notable of these... (Review)
Review
JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in immune-compromised individuals. The most notable of these JCPyV-associated CNS diseases is the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML). PML, an AIDS-defining disease in the pre-cART epoch, has emerged as a life-threatening complication in patients receiving immunomodulatory agents for autoimmune and inflammatory disorders and treatment for certain hematological malignancies. Among the rapidly expanding list of PML-associated biologics, natalizumab (Tysabri®) has the highest incidence and is an ominous sequela for multiple sclerosis (MS) patients who otherwise benefit from dramatic reductions in relapses using this immunomodulatory agent. Drug withdrawal, the only therapeutic option for PML, is often complicated by a high-mortality cerebral inflammatory reaction. No anti-JCPyV agents are available. Lack of a tractable animal model of polyomavirus-induced central nervous system (CNS) disease is an acknowledged bottleneck to elucidating PML pathogenesis, immunological mechanisms that control JCPyV, in vivo evaluation of agents that inhibit polyomavirus replication in tissue culture, and uncovering early events that presage JCPyV-associated neuropathology. The natural virus-host mouse polyomavirus (MuPyV) model has recently been developed to explore mechanisms of polyomavirus-associated CNS disease. In this review, we will cover the benefits of using the MuPyV model to answer fundamental questions about innate and adaptive immune control of JCPyV, the impact of immunomodulation on JCPyV pathogenesis, and how this MuPyV CNS infection model will help improve criteria for identifying patients at risk for JCPyV-associated CNS diseases before the development of irreversible lesions.
Topics: Animals; Biological Products; Disease Models, Animal; Humans; Immunomodulating Agents; JC Virus; Leukoencephalopathy, Progressive Multifocal; Mice; Natalizumab; Polyomavirus
PubMed: 34145975
DOI: 10.1111/febs.16083 -
Clinical & Developmental Immunology 2013JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct,... (Review)
Review
JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct, immunocompromised patient cohorts. The recent discoveries of eight new members of the Polyomaviridae family that are capable of infecting humans suggest that there are more to be discovered and raise the possibility that they may play a more significant role in human disease than previously understood. In spite of this, there remains a dearth of specific therapeutic options for human polyomavirus infections and an incomplete understanding of the relationship between the virus and the host immune system. This review summarises the human polyomaviruses with particular emphasis on pathogenesis in those directly implicated in disease aetiology and the therapeutic options available for treatment in the immunocompromised host.
Topics: Antiviral Agents; BK Virus; Genome, Viral; Humans; Immune Evasion; Immune System; Immunocompromised Host; JC Virus; Phylogeny; Polyomaviridae; Polyomavirus Infections; RNA, Viral; Tumor Virus Infections; Virus Activation
PubMed: 23737811
DOI: 10.1155/2013/373579 -
AIDS Research and Therapy Jul 2020The human neurotropic virus JC Polyomavirus, a member of the Polyomaviridae family, is the opportunistic infectious agent causing progressive multifocal... (Review)
Review
The human neurotropic virus JC Polyomavirus, a member of the Polyomaviridae family, is the opportunistic infectious agent causing progressive multifocal leukoencephalopathy, typically in immunocompromised individuals. The spectrum of underlying reasons for the systemic immunosuppression that permits JCV infection in the central nervous system has evolved over the past 2 decades, and therapeutic immunosuppression arousing JCV infection in the brain has become increasingly prominent as a trigger for PML. Effective immune restoration subsequent to human immunodeficiency virus-related suppression is now recognized as a cause for unexpected deterioration of symptoms in patients with PML, secondary to a rebound inflammatory phenomenon called immune reconstitution inflammatory syndrome, resulting in significantly increased morbidity and mortality in a disease already infamous for its lethality. This review addresses current knowledge regarding JC Polyomavirus, progressive multifocal leukoencephalopathy, progressive multifocal leukoencephalopathy-related immune reconstitution inflammatory syndrome, and the immunocompromised states that incite JC Polyomavirus central nervous system infection, and discusses prospects for the future management of these conditions.
Topics: Central Nervous System Viral Diseases; HIV Infections; Humans; Immune Reconstitution Inflammatory Syndrome; Immunocompromised Host; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 32631361
DOI: 10.1186/s12981-020-00293-0 -
Annals of Neurology Apr 2015Many neurological diseases of the central nervous system (CNS) are underpinned by malfunctions of the immune system, including disorders involving opportunistic... (Review)
Review
Many neurological diseases of the central nervous system (CNS) are underpinned by malfunctions of the immune system, including disorders involving opportunistic infections. Progressive multifocal leukoencephalopathy (PML) is a lethal CNS demyelinating disease caused by the human neurotropic polyomavirus JC (JCV) and is found almost exclusively in individuals with immune disruption, including patients with human immunodeficiency virus/acquired immunodeficiency syndrome, patients receiving therapeutic immunomodulatory monoclonal antibodies to treat conditions such as multiple sclerosis, and transplant recipients. Thus, the public health significance of this disease is high, because of the number of individuals constituting the at-risk population. The incidence of PML is very low, whereas seroprevalence for the virus is high, suggesting infection by the virus is very common, and so it is thought that the virus is restrained but it persists in an asymptomatic state that can only occasionally be disrupted to lead to viral reactivation and PML. When JCV actively replicates in oligodendrocytes and astrocytes of the CNS, it produces cytolysis, leading to formation of demyelinated lesions with devastating consequences. Defining the molecular nature of persistence and events leading to reactivation of the virus to cause PML has proved to be elusive. In this review, we examine the current state of knowledge of the JCV life cycle and mechanisms of pathogenesis. We will discuss the normal course of the JCV life cycle including transmission, primary infection, viremia, and establishment of asymptomatic persistence as well as pathogenic events including migration of the virus to the brain, reactivation from persistence, viral infection, and replication in the glial cells of the CNS and escape from immunosurveillance.
Topics: Animals; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Seroepidemiologic Studies
PubMed: 25623836
DOI: 10.1002/ana.24371