Infection Of Oligodendrocytes Research Articles

Molecular determinants of alphavirus neuropathogenesis in mice.

Alphaviruses are enveloped viruses with a positive-stranded RNA genome, of the family Togaviridae. In mammals and birds they are mosquito-transmitted and are of veterinary and medical importance. They cause primarily two types of disease: encephalitis and polyarthritis. Here we review attempts to understand the molecular basis of encephalitis and virulence for the central nervous system (CNS) in mouse models. Sindbis virus (SINV) was the first virus to be studied in this way. Other viruses analysed are Semliki Forest virus (SFV), Venezuelan equine encephalitis virus, Eastern equine encephalitis virus and Western equine encephalitis virus. Neurovirulence was found to be associated with damage to neurons in the CNS. It mapped mainly to the E2 region of the genome, and to the nsP3 gene. Also, avirulent natural isolates of both SINV and SFV have been found to have more rapid cleavage of nonstructural proteins due to mutations in the nsP1-nsP2 cleavage site. Immune-mediated demyelination for avirulent SFV has been shown to be associated with infection of oligodendrocytes. For Chikungunya virus, an emerging alphavirus that uncommonly causes encephalitis, analysis of the molecular basis of CNS pathogenicity is beginning. Experiments on SINV and SFV have indicated that virulence may be related to the resistance of virulent virus to interferon action. Although the E2 protein may be involved in tropism for neurons and passage across the blood-brain barrier, the role of the nsP3 protein during infection of neurons is unknown. More information in these areas may help to further explain the neurovirulence of alphaviruses.

Immune suppression of JC virus gene expression is mediated by SRSF1.

Progressive multifocal leukoemcephalopathy (PML) is a fatal demyelinating disease caused by the human neurotropic JC virus (JCV). JCV infects the majority of the human population during childhood and establishes a latent/persistent life-long infection. The virus reactivates under immunosuppressive conditions by unknown mechanisms, resulting in productive infection of oligodendrocytes in the central nervous system (CNS). Given the fact that the natural occurrence of PML is strongly associated with immunosuppression, the functional and molecular interaction between glial cells and neuroimmune signaling mediated by soluble immune mediators is likely to play a major role in reactivation of JCV and the progression of the lytic viral life cycle leading to the development of PML. In order to explore the effect of soluble immune mediators secreted by peripheral blood mononuclear cells (PBMCs) on JCV transcription, primary human fetal glial (PHFG) cells were treated with conditioned media from PBMCs. We observed a strong suppression of JCV early as well as late gene transcription in cells treated with conditioned media from induced PBMCs. Using a variety of virological and molecular biological approaches, we demonstrate that immune mediators secreted by PBMCs induce the expression of SRSF1, a strong inhibitor of JCV gene expression, and inhibit the replication of JCV. Our results show that downregulation of SRSF1 in glial cells overcomes the suppression of JCV gene expression and its replication mediated by soluble immune mediators. These findings suggest the presence of a novel immune signaling pathway between glial cells and PBMCs that may control JCV gene expression during the course of viral reactivation.

Polyomavirus-associated progressive multifocal leukoencephalopathy (PML) in HAART era.

Polyomaviruses may cause human disease, particularly in immunocompromised hosts. JCV, one of the members of polyomaviridae family, is the causative agent of the neurological disease progressive multifocal leukoencephalopathy (PML), which occurs mostly in immunocompromised patients. Progressive Multifocal leukoencephalopathy (PML) is a progressive demyelinating disorder of the central nervous system (CNS) resulting from infection of oligodendrocytes by JC polyomavirus. Whereas after highly active antiretroviral therapy (HAART), the incidence of nearly all of all neurological complication have decreased, this article evaluates the incidence and prognosis of JC polyomavirus-associated PML including a unchangeable incidence of PML associated with JC polyomavirus compared with other opportunistic disease and paradoxical results of disease remission in HAART era.

Progressive multifocal leukoencephalopathy: A review

Progressive Multifocal Leukoencephalopathy is a demyelinating disease of the Central Nervous System characterized by widespread lesions due to infection of oligodendrocytes by JC (John Cunningham) virus. Neurological manifestations of JCV induced tissue damage include the classic triad of presenting symptoms of PML. These are visual, motor, and cognitive impairments. In 40% of the initial symptoms, Hemianopsia or the loss of vision in the bisection of the visual field is the most common. In greater than 50% of the cases, severe muscle weakness progressing into hemiparesis or hemiplegia is present. The diagnosis of PML is most appropriately done by brain imaging technique. A classic triad of demyelination, bizarre astrocytes, and oligodendroglial nuclear inclusions include the histopathology of PML. Both serum and CSF should be examined for antibodies against JCV before going for a Brain biopsy. All treatments are exploratory in progressive multifocal Leukoencephalopathy (PML). In PML patients with undetectable plasma HIV, Intensive treatment with 4 classes of antiretroviral drugs, including enfuvirtide, has been reported as delivering a possible survival benefit. Treatment guidelines consider the use of corticosteroids justified in this setting. Further approaches to the isolation of virus and the immunization against the virus may arrest the progression of PML and its deadly complications.

Gliopathy of Demyelinating and Non-Demyelinating Strains of Mouse Hepatitis Virus

Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV) is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59) and non-demyelinating (RSMHV2) viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination. In vivo, RSA59 infection was identified in spinal cord gray and white matter, but infected oligodendrocytes were restricted to white matter. In contrast, RSMHV2 infection was restricted to gray matter neurons and was not localized to oligodendrocytes. In vitro, RSA59 can infect both oligodendrocyte precursors and differentiated oligodendrocytes, whereas RSMHV2 can infect oligodendrocyte precursors but not differentiated oligodendrocytes. Viral spreading through axonal means to white matter and release of the demyelinating strain MHV at the nerve end is critical for oligodendrocytes infection and subsequent demyelination. Understanding the mechanisms by which known viruses effect demyelination in this animal model has important therapeutic implications in the treatment of human demyelinating disease.

Simian Virus 40 Infection in the Spinal Cord of Simian Immunodeficiency Virus-Immunosuppressed Rhesus Macaques.

Progressive multifocal leukoencephalopathy (PML) is an often-fatal demyelinating disease of the CNS that usually develops in immunocompromised individuals because of reactivation of quiescent JC virus (JCV). There are only a few reports of JCV infection in the human spinal cord. Progressive multifocal leukoencephalopathy-like demyelinating lesions have been documented in the brains of simian immunodeficiency virus-infected macaques. To determine whether simian virus 40 (SV40) can infect and cause PML lesions in spinal cords of immunosuppressed macaques, we examined archival spinal cord samples from 15 simian immunodeficiency virus-infected rhesus monkeys with acquired immunodeficiency syndrome and SV40 infection of the brain. Among those, 6 (40%) had SV40-infected cells in the spinal cord, including 1 with PML-like lesions, 1 with PML-like lesions and meningoencephalitis, 2 with meningoencephalitis, 1 with gray matter gliosis, and 1 with no lesions. One animal with a large PML-like lesion had extensive demyelination and SV40 infection of astrocytes, oligodendrocytes, and meningeal cells. None of the 6 animals had SV40-infected spinal cord neurons. These observations indicate that, like JCV in immunosuppressed humans, SV40 can infect glial cells and cause PML-like lesions in the spinal cord of immunosuppressed rhesus macaques. Rhesus macaques could serve as an animal model to study polyomavirus infection and pathogenesis in the spinal cord.

Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS).

Progressive multifocal leukoencephalopathy is a viral encephalitis induced by the John Cunningham (JC) virus, an ubiquitous neurotropic papovavirus of the genus polyomavirus that in healthy people in latency resides in kidney and bone marrow cells. Activation and entry into the CNS were first seen in patients with malignancies of the hematopoietic system and an impaired immune system. During the 1980 and the 1990s with the appearance of human immunodeficiency virus infection in humans, PML was found to be the most important opportunistic infection of the central nervous system. As a result of highly efficient immunosuppressive and immunomodulatory treatments, in recent years, the number of PML cases again increased. PML is prevented by an intact cellular immune response and accordingly immune reconstitution can terminate established disease in the CNS. However, forced immune reconstitution can lead to massive destruction of virus-infected cells. This may result in clinical exacerbation associated with high morbidity and mortality and referred to as PML with immune reconstitution inflammatory syndrome (PML-IRIS). In the present review, we discuss virological properties and routes of infection in the CNS, but mostly focus on the pathology of PML and PML-IRIS and on the role of the immune system in these disorders. We show that PML and PML-IRIS result from predominant JC virus infection of oligodendrocytes and, to a lesser extent, of infected neurons. Inflammation in these encephalitides seems to be driven by a dominant cytotoxic T cell response which is massively exaggerated during IRIS.

IFN-Gamma Inhibits JC Virus Replication in Glial Cells by Suppressing T-Antigen Expression.

ObjectivePatients undergoing immune modulatory therapies for the treatment of autoimmune diseases such as multiple sclerosis, and individuals with an impaired-immune system, most notably AIDS patients, are in the high risk group of developing progressive multifocal leukoencephalopathy (PML), an often lethal disease of the brain characterized by lytic infection of oligodendrocytes in the central nervous system (CNS) with JC virus (JCV). The immune system plays an important regulatory role in controlling JCV reactivation from latent sites by limiting viral gene expression and replication. However, little is known regarding the molecular mechanisms responsible for this regulation.Methods and ResultsHere, we investigated the impact of soluble immune mediators secreted by activated PBMCs on viral replication and gene expression by cell culture models and molecular virology techniques. Our data revealed that viral gene expression and viral replication were suppressed by soluble immune mediators. Further studies demonstrated that soluble immune mediators secreted by activated PBMCs inhibit viral replication induced by T-antigen, the major viral regulatory protein, by suppressing its expression in glial cells. This unexpected suppression of T-antigen was mainly associated with the suppression of translational initiation. Cytokine/chemokine array studies using conditioned media from activated PBMCs revealed several candidate cytokines with possible roles in this regulation. Among them, only IFN-γ showed a robust inhibition of T-antigen expression. While potential roles for IFN-β, and to a lesser extent IFN-α have been described for JCV, IFN-γ has not been previously implicated. Further analysis of IFN-γ signaling pathway revealed a novel role of Jak1 signaling in control of viral T-antigen expression. Furthermore, IFN-γ suppressed JCV replication and viral propagation in primary human fetal glial cells, and showed a strong anti-JCV activity.ConclusionsOur results suggest a novel role for IFN-γ in the regulation of JCV gene expression via downregulation of the major viral regulatory protein, T-antigen, and provide a new avenue of research to understand molecular mechanisms for downregulation of viral reactivation that may lead to development of novel strategies for the treatment of PML.

Human Polyomavirus Receptor Distribution in Brain Parenchyma Contrasts with Receptor Distribution in Kidney and Choroid Plexus

The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy, a rare demyelinating disease that occurs in the setting of prolonged immunosuppression. After initial asymptomatic infection, the virus establishes lifelong persistence in the kidney and possibly other extraneural sites. In rare instances, the virus traffics to the central nervous system, where oligodendrocytes, astrocytes, and glial precursors are susceptible to lytic infection, resulting in progressive multifocal leukoencephalopathy. The mechanisms by which the virus traffics to the central nervous system from peripheral sites remain unknown. Lactoseries tetrasaccharide c (LSTc), a pentasaccharide containing a terminal α2,6-linked sialic acid, is the major attachment receptor for polyomavirus. In addition to LSTc, type 2 serotonin receptors are required for facilitating virus entry into susceptible cells. We studied the distribution of virus receptors in kidney and brain using lectins, antibodies, and labeled virus. The distribution of LSTc, serotonin receptors, and virus binding sites overlapped in kidney and in the choroid plexus. In brain parenchyma, serotonin receptors were expressed on oligodendrocytes and astrocytes, but these cells were negative for LSTc and did not bind virus. LSTc was instead found on microglia and vascular endothelium, to which virus bound abundantly. Receptor distribution was not changed in the brains of patients with progressive multifocal leukoencephalopathy. Virus infection of oligodendrocytes and astrocytes during disease progression is LSTc independent.

Immune System Involvement in the Pathogenesis of JC Virus Induced PML: What is Learned from Studies of Patients with Underlying Diseases and Therapies as Risk Factors.

The human polyomavirus JC PyV lytic infection of oligodendrocytes in the human brain results in the demyelinating disease progressive multifocal leukoencephalopathy, PML. JCV is a common virus infection in the population that leads to PML in patients with underlying diseases and therapies that cause immune deficiencies or modulate immune system functions. Patients may have high levels of antibody to JCV that neither protect them from PML nor clear the infection once PML is established. Cell-mediated immunity plays a more effective role in clearing initial or reactivated JCV infection before PML occurs. However, patients with underlying diseases and therapies for treatment are at high risk for PML. MS patients on natalizumab are one of the categories with the highest incidence of PML. Natalizumab is a humanized monoclonal antibody targeting α4 integrins that prevents inflammatory cells from entering the brain and it has been used as a treatment for MS. A number of studies have investigated the occurrence of PML in these patients and their cell-mediated immune profile that might gain insight into the mechanism that ties natalizumab with a high risk of developing PML. It seems that cells of the immune system participate in the pathogenesis of PML as well as clearance of JCV infection.

The importance of mouse models to define immunovirologic determinants of progressive multifocal leukoencephalopathy.

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.

An Unusual Case of Progressive Multifocal Leukoencephalopathy in a Patient with Non-traditional Risk Factors

Progressive multifocal leukoencephalopathy (PML) is a frequently fatal demyelinating condition of the central nervous system in which reactivation of the human polyomavirus JC (JCV) leads to lytic infection of oligodendrocytes. JCV reactivation typically occurs in the setting of profound impairment of cellular immunity seen in conditions such as human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS), hematologic malignancies, autoimmune diseases, and treatment with immunosuppressive medications. However, an emerging body of literature suggests that minimal or occult immunosuppression may be sufficient for the development of PML in certain cases. We report the case of a 52 year old man diagnosed with PML without history of or risk factors for immunocompromise, with absolute number of CD4 + T cells below the lower limit of normal but not meeting criteria for idiopathic CD4+ lymphocytopenia (ICL), who was subsequently found to have evidence of hepatic cirrhosis of unclear etiology. This is only the eighth case published of hepatic cirrhosis as the main identifiable risk factor for the development of PML and informs the ongoing discussion on mechanisms of moderate immunocompromise sufficient to allow for occurrence of this disease.

JC virus quasispecies analysis reveals a complex viral population underlying progressive multifocal leukoencephalopathy and supports viral dissemination via the hematogenous route.

Opportunistic infection of oligodendrocytes by human JC polyomavirus may result in the development of progressive multifocal encephalopathy in immunocompromised individuals. Neurotropic JC virus generally harbors reorganized noncoding control region (NCCR) DNA interspersed on the viral genome between early and late coding genes. By applying 454 sequencing on NCCR DNA amplified from body fluid samples (urine, plasma, and cerebrospinal fluid [CSF]) from 19 progressive multifocal leukoencephalopathy (PML) patients, we attempted to reveal the composition of the JC polyomavirus population (the quasispecies, i.e., the whole of the consensus population and minor viral variants) contained in different body compartments and to better understand intrapatient viral dissemination. Our data demonstrate that in the CSF of PML patients, the JC viral population is often a complex mixture composed of multiple viral variants that contribute to the quasispecies. In contrast, urinary JC virus highly resembled the archetype virus, and urine most often did not contain minor viral variants. It also appeared that archetype JC virus could sporadically be identified in PML patient brain, although selection of rearranged JC virus DNA was favored. Comparison of the quasispecies from different body compartments within a given patient suggested a strong correlation between the viral population in plasma and CSF, whereas the viral population shed in urine appeared to be unrelated. In conclusion, it is shown that the representation of viral DNA in the CSF following the high-level DNA replication in the brain underlying PML has hitherto been much underestimated. Our data also underscore that the hematogenous route might play a pivotal role in viral dissemination from or toward the brain. For the first time, the JC polyomavirus population contained in different body compartments of patients diagnosed with progressive multifocal encephalopathy has been studied by deep sequencing. Two main findings came out of this work. First, it became apparent that the complexity of the viral population associated with PML has been highly underestimated so far, suggestive of a highly dynamic process of reorganization of the noncoding control region of JC polyomavirus in vivo, mainly in CSF and blood. Second, evidence showing viral dissemination from and/or toward the brain via the hematogenous route was provided, confirming a hypothesis that was recently put forward in the field.

JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50–60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10−15) and controls (OR = 0.53, p = 2×10−5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10−5). The German dataset confirmed these findings (OR = 0.54, p = 1×10−4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.

Quasispecies Analysis of JC Virus DNA Present in Urine of Healthy Subjects

JC virus is a human polyomavirus that infects the majority of people without apparent symptoms in healthy subjects and it is the causative agent of progressive multifocal leucoencephalopathy (PML), a disorder following lytic infection of oligodendrocytes that mainly manifests itself under immunosuppressive conditions. A hallmark for JC virus isolated from PML-brain is the presence of rearrangements in the non-coding control region (NCCR) interspersed between the early and late genes on the viral genome. Such rearrangements are believed to originate from the archetype JC virus which is shed in urine by healthy subjects and PML patients. We applied next generation sequencing to explore the non-coding control region variability in urine of healthy subjects in search for JC virus quasispecies and rearrangements reminiscent of PML. For 61 viral shedders (out of a total of 254 healthy subjects) non-coding control region DNA and VP1 (major capsid protein) coding sequences were initially obtained by Sanger sequencing. Deletions between 1 and 28 nucleotides long appeared in ∼24.5% of the NCCR sequences while insertions were only detected in ∼3.3% of the samples. 454 pyrosequencing was applied on a subset of 54 urine samples demonstrating the existence of JC virus quasispecies in four subjects (∼7.4%). Hence, our results indicate that JC virus DNA in urine is not always restricted to one unique virus variant, but can be a mixture of naturally occurring variants (quasispecies) reflecting the susceptibility of the non-coding control region for genomic rearrangements in healthy individuals. Our findings pave the way to explore the presence of viral quasispecies and the altered viral tropism that might go along with it as a potential risk factor for opportunistic secondary infections such as PML.

Polyomavirus JC in the Context of Immunosuppression: A Series of Adaptive, DNA Replication-Driven Recombination Events in the Development of Progressive Multifocal Leukoencephalopathy

Polyomavirus JC (JCV) is the etiological agent of progressive multifocal leukoencephalopathy (PML), a demyelinating infection of oligodendrocytes in the brain. PML, a frequently fatal opportunistic infection in AIDS, has also emerged as a consequence of treatment with several new immunosuppressive therapeutic agents. Although nearly 80% of adults are seropositive, JCV attains an ability to infect glial cells in only a minority of people. Data suggest that JCV undergoes sequence alterations that accompany this ability, and these changes can be derived from an archetype strain by mutation, deletion, and duplication. While the introductory source and primary tissue reservoir of JCV remain unknown, lymphoid cells have been identified as potential intermediaries in progression of JCV to the brain. This review is focused on sequence changes in the noncoding control region (NCCR) of the virus. We propose an adaptive mechanism that involves a sequential series of DNA replication-driven NCCR recombination events involving stalled DNA replication forks at NCCR palindromic secondary structures. We shall describe how the NCCR sequence changes point to a model in which viral DNA replication drives NCCR recombination, allowing JCV adaptation to different cell types in its progression to neurovirulence.

Attenuation of Semliki Forest Virus Neurovirulence by MicroRNA-Mediated Detargeting

Artificial target sequences for tissue-specific miRNAs have recently been introduced as a new means for altering the tissue tropism of viral replication. This approach can be used to improve the safety of oncolytic viruses for cancer virotherapy by restricting their replication in unwanted tissues, such as the liver. Semliki Forest virus (SFV) is a positive-strand RNA virus and, similar to the related alphaviruses, like Sindbis virus, has potential as a gene therapy vector and an oncolytic virotherapy agent, but this potential is limited by the neurovirulence of these alphaviruses. Here, we have generated a replicative SFV4 carrying six tandem targets for the neuron-specific miR124 between the viral nonstructural protein 3 and 4 (nsp3 and nsp4) genes. When administered intraperitoneally into adult BALB/c mice, SFV4-miRT124 displayed an attenuated spread into the central nervous system (CNS) and greatly increased survival. Peripheral replication was not affected, indicating neuron-specific attenuation. Moreover, a strong protective SFV immunity was elicited in these animals. Intracranial infection of adult mice with SFV4-miRT124 showed greatly reduced infection of neurons in the brain but led to the infection of oligodendrocytes in the corpus callosum. Taken together, our data show that miR124-mediated attenuation of neurovirulence is a feasible and promising strategy for generating safer oncolytic alphavirus virotherapy agents.

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

Human polyomavirus JC reactivation and pathogenetic mechanisms of progressive multifocal leukoencephalopathy and cancer in the era of monoclonal antibody therapies

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the neurotropic human polyomavirus JC (JCV) lytic infection of oligodendrocytes. PML was first described as a complication of lymphoproliferative disorders more than 50 years ago and emerged as a major complication of human immunodeficiency virus (HIV) infection in the 1980s. Despite the ubiquity of this virus, PML is rare and always seen in association with underlying immunosuppressive condition, such as HIV infection, autoimmune diseases, cancer, and organ transplantation. JCV remains quiescent in the kidneys, where it displays a stable archetypal non-coding control region (NCCR). Conversely, rearranged JCV NCCR, including tandem repeat patterns found in the brain of PML patients, have been associated with neurovirulence. The specific site and mechanism of JCV NCCR transformation is unknown. According to one model, during the course of immunosuppression, JCV departs from its latent state and after entering the brain, productively infects and destroys oligodendrocytes. Although the majority of PML cases occur in severely immunesuppressed individuals, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies (mAbs) that modulate immune system functions: in fact, CD4+ and CD8+ T lymphopenia, resulting from this immunomodulatory therapy, are the primary risk factor. Furthermore, JCV reactivation in nonpermissive cells after treatment with mAbs, such as intestinal epithelial cells in Crohn's disease patients, in association with other host tumor-inducing factors, could provide valid information on the role of JCV in several malignancies, such as colorectal cancer.

Progressive Multifocal Leukoencephalitis In A Patient With Systemic Lupus Erythematosus On Hydroxychloroquine

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system. Reactivation of the polyomavirus JC in immunosuppressed patients induces a lytic infection of oligodendrocytes. The disease is usually fatal in a few months and survivors experience severe neurologic deficits. It is well known to be associated with conditions such as HIV, malignancies, organ transplant recipients and those with chronic inflammatory diseases on immunosuppressive therapy. Review of the medical literature revealed only a few case reports of this disease occurring in minimally immunosuppressed patients (1,3,6). We report a patient with systemic lupus erythematosus on minimal iatrogenic immunosuppression that subsequently developed PML.