-
Arquivos de Neuro-psiquiatria Sep 2013Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by reactivation of JC virus (JCV) in a setting of cellular... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by reactivation of JC virus (JCV) in a setting of cellular immunosuppression. Originally, PML was observed in patients with advanced HIV infection, lymphoproliferative disorders and transplant recipients. However, the widespread use of HIV antiretroviral drugs and the new selective immunomodulatory and immunosuppressive medications, such as Rituximab and Natalizumab, has recently modified the epidemiology, clinical presentation and prognosis of PML. Herein, we discuss the new concepts on PML, emphasizing the recent modification in the epidemiology; the impact of new immunomodulatory treatments in the disease, PML-IRIS (Immune reconstitution inflammatory syndrome), new treatment strategies and other JCV related CNS diseases.
Topics: Antiretroviral Therapy, Highly Active; Humans; Immune Reconstitution Inflammatory Syndrome; Immunosuppressive Agents; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 24141508
DOI: 10.1590/0004-282X20130154 -
APMIS : Acta Pathologica,... Aug 2013For almost 40 years, polyomavirus JC and BK were the only known human polyomaviruses but in the last 7 years, increased interest and innovative molecular screening...
For almost 40 years, polyomavirus JC and BK were the only known human polyomaviruses but in the last 7 years, increased interest and innovative molecular screening techniques have led to the identification of 10 previously unknown polyomaviruses in humans. Two of these, Merkel cell polyomavirus and Trichodysplasia spinulosa polyomavirus, have also been found to cause disease in immunocompromised patients. Seroprevalence studies indicate that human polyomaviruses are transmitted independently of one another in humans and carry different risks of exposure and reexposure throughout life. The potential coexistence of 12 or more different polyomavirus species in the same host and possibly even in the same organ raises the question of potential interactions. Careful review of polyomavirus biology may facilitate new discoveries concerning these formerly underestimated viral agents and their influence on human health.
Topics: BK Virus; Humans; Immunocompromised Host; JC Virus; Polyomavirus Infections; Seroepidemiologic Studies
PubMed: 23781946
DOI: 10.1111/apm.12125 -
The Journal of Infectious Diseases Mar 2011Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is rare even though the proven etiological agent of PML,... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that is rare even though the proven etiological agent of PML, the polyomavirus JC (JC virus), is ubiquitous within the human population. The common feature of PML cases appears to be underlying immunosuppression, and PML has gained clinical visibility because of its association with human immunodeficiency virus and AIDS and its occurrence as a side effect of certain immunomodulatory drugs. A hypothesis has gained general acceptance that JC virus causes a primary infection in childhood and enters a latent state, after which immunosuppression allows viral reactivation leading to PML. Nonetheless, many important aspects of PML pathogenesis remain unclear, including the molecular bases of latency and reactivation, the site(s) of latency, the relationship of archetype and prototype virus and the mode of virus transmission within the body and between individuals. In this review, we will revisit these areas and examine what the available evidence suggests.
Topics: Antibodies, Viral; Humans; Immune Tolerance; JC Virus; Leukoencephalopathy, Progressive Multifocal; Palatine Tonsil; Virus Activation; Virus Latency
PubMed: 21227915
DOI: 10.1093/infdis/jiq097 -
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 -
The Canadian Journal of Neurological... Jul 2011Monoclonal antibodies have become an important treatment option for a number of serious conditions. Concerns have arisen about the potential association of these... (Review)
Review
Monoclonal antibodies have become an important treatment option for a number of serious conditions. Concerns have arisen about the potential association of these products with progressive multifocal leukoencephalopathy (PML). A list of monoclonal antibodies authorized for sale was derived from the Health Canada Drug Product Database. Case reports of PML after exposure to a monoclonal antibody authorized for use in Canada were retrieved by searching Canada Vigilance and WHO adverse event databases and through a Pub MED/Medline literature search. 182 adverse event case reports were retrieved (adalimumab -1 case, alemtuzumab-14, bevacizumab -3, cetuximab -1, efalizumab - 8, ibritumomab tiuxetan-5, infliximab-4, natalizumab-32, and rituximab-114). The Canadian Product Monographs for natalizumab and ritiximab contain box warnings for PML. A natalizumab registry has been established.
Topics: Adverse Drug Reaction Reporting Systems; Antibodies, Monoclonal; Canada; Databases, Factual; Humans; Immunologic Factors; JC Virus; Leukoencephalopathy, Progressive Multifocal
PubMed: 21672696
DOI: 10.1017/s0317167100012105 -
Viruses Sep 2020In the fifty years since the discovery of JC polyomavirus (JCPyV), the body of research representing our collective knowledge on this virus has grown substantially. As... (Review)
Review
In the fifty years since the discovery of JC polyomavirus (JCPyV), the body of research representing our collective knowledge on this virus has grown substantially. As the causative agent of progressive multifocal leukoencephalopathy (PML), an often fatal central nervous system disease, JCPyV remains enigmatic in its ability to live a dual lifestyle. In most individuals, JCPyV reproduces benignly in renal tissues, but in a subset of immunocompromised individuals, JCPyV undergoes rearrangement and begins lytic infection of the central nervous system, subsequently becoming highly debilitating-and in many cases, deadly. Understanding the mechanisms allowing this process to occur is vital to the development of new and more effective diagnosis and treatment options for those at risk of developing PML. Here, we discuss the current state of affairs with regards to JCPyV and PML; first summarizing the history of PML as a disease and then discussing current treatment options and the viral biology of JCPyV as we understand it. We highlight the foundational research published in recent years on PML and JCPyV and attempt to outline which next steps are most necessary to reduce the disease burden of PML in populations at risk.
Topics: Animals; History, 20th Century; History, 21st Century; Humans; JC Virus; Polyomavirus Infections; Tumor Virus Infections
PubMed: 32882975
DOI: 10.3390/v12090969 -
The New England Journal of Medicine Apr 2019
Topics: Antibodies, Monoclonal, Humanized; Humans; JC Virus; Leukoencephalopathy, Progressive Multifocal; Natalizumab
PubMed: 30969502
DOI: 10.1056/NEJMe1904140 -
Cell Reports May 2019JC polyomavirus (JCPyV) is a ubiquitous human pathogen that causes progressive multifocal leukoencephalopathy (PML). The entry receptors for JCPyV belong to the...
JC polyomavirus (JCPyV) is a ubiquitous human pathogen that causes progressive multifocal leukoencephalopathy (PML). The entry receptors for JCPyV belong to the 5-hydroxytryptamine 2 receptor (5-HTR) family, but how individual members of the family function to facilitate infection is not known. We used proximity ligation assay (PLA) to determine that JCPyV interacts with each of the 5-HT receptors (5-HTRs) in a narrow window of time during entry. We used CRISPR-Cas9 to randomly introduce stop codons in the gene for each receptor and discovered that the second intracellular loop of each was necessary for infection. This loop contains a motif possibly involved in receptor internalization by β-arrestin. Mutation of this motif and small interfering RNA (siRNA) knockdown of β-arrestin recapitulated the results of our CRISPR-Cas9 screen, showing that this motif is critical. Our results have implications for the role these receptors play in virus infection and for their normal functioning as receptors for serotonin.
Topics: HEK293 Cells; Host-Pathogen Interactions; Humans; JC Virus; Receptors, Serotonin, 5-HT2; Receptors, Virus; Virus Internalization; beta-Arrestins
PubMed: 31091436
DOI: 10.1016/j.celrep.2019.04.067 -
The Journal of Infectious Diseases Dec 1997JC virus (JCV), the causative agent of the fatal human demyelinating disease progressive multifocal leukoencephalopathy (PML), is an opportunistic papovavirus that... (Review)
Review
JC virus (JCV), the causative agent of the fatal human demyelinating disease progressive multifocal leukoencephalopathy (PML), is an opportunistic papovavirus that infects and destroys oligodendrocytes, the myelin-producing cells of the central nervous system. Since its isolation from the brain of a PML patient, JCV has long been classed as a neurotropic virus. Many studies, however, have demonstrated that JCV can infect various other cell types, including immune system cells. Moreover, several recent studies have focused specifically on lymphocytes as a target of JCV. This review chronicles the association of JCV with lymphocytes, including cell type localization, molecular regulation, and viral sequences, and discusses clinical implications of these findings.
Topics: Antigens, Viral; Blood Cells; Bone Marrow Cells; Brain; DNA, Viral; Humans; JC Virus; Lymphocytes; Papillomavirus Infections; Tumor Virus Infections
PubMed: 9395374
DOI: 10.1086/514161 -
Molecular Ecology Apr 2004Viruses, especially those with RNA genomes, represent ideal organisms to study the dynamics of microevolutionary change. In particular, their rapid rate of nucleotide... (Review)
Review
Viruses, especially those with RNA genomes, represent ideal organisms to study the dynamics of microevolutionary change. In particular, their rapid rate of nucleotide substitution means that the epidemiological processes that shape their diversity act on the same time-scale as mutations are fixed in viral populations. Consequently, the branching structure of virus phylogenies provides a unique insight into spatial and temporal dynamics. Herein, I describe the key processes in virus phylogeography. These are generally associated with the relative rates of dispersal among populations and virus-host codivergence (vicariance), and the division between acute (short-term) and persistent (long-term) infections. These processes will be illustrated by important human viruses - HIV, dengue, rabies, polyomavirus JC and human papillomavirus - which display varying spatial and temporal structures and virus-host relationships. Key research questions for the future will also be established.
Topics: Dengue Virus; Evolution, Molecular; Geography; HIV; Humans; JC Virus; Mutation; Papillomaviridae; Phylogeny; Population Dynamics; RNA Viruses; Rabies virus
PubMed: 15012753
DOI: 10.1046/j.1365-294x.2003.02051.x