Spinal cord involvement in progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infectious demyelinating disease of the central nervous system caused by JC polyomavirus predominantly affecting immunocompromised individuals. Nowadays, HIV, hematological malignancies and iatrogenic immune suppression account for most PML cases. For unknown reasons, spinal cord is classically protected from PML lesions. Here, we report the course of a patient harboring spinal cord lesions in the context of PML with immune reconstitution inflammatory syndrome and review the eight other cases reported in the literature so far. Then, we discuss the evolving spectrum of PML over recent years, potentially making its diagnosis more challenging.

Progressive multifocal leukoencephalopathy associated with systemic lupus erythematosus: longitudinal observation of lymphocytes, JC virus in cerebrospinal fluid, and brain magnetic resonance imaging.

Progressive multifocal leukoencephalopathy (PML) rarely occurs in patients with systemic lupus erythematosus (SLE). This report presents the case of a patient who developed PML due to SLE-associated multiple factors. A 60-year-old woman diagnosed with SLE undergoing multiple immunosuppressive therapies, including azathioprine, presented with cerebral cortical symptoms, lymphocytopenia, and vitamin B12 deficiency and was subsequently diagnosed with SLE-associated PML. We evaluated the cause and disease activity of PML, focusing on the longitudinal assessment of lymphocytopenia, JC virus (JCV) DNA copy number in the cerebrospinal fluid, and magnetic resonance imaging (MRI) findings. Discontinuing azathioprine and initiating alternative immunosuppressive treatments with intramuscular vitamin B12 injections affected lymphocytopenia and disease management. However, despite recovery from lymphopenia and JCV DNA copy number being low, the large hyperintense and punctate lesions observed on the fluid-attenuated inversion recovery (FLAIR) images exhibited varying behaviors, indicating that the balance between contributing factors for PML may have fluctuated after the initial treatment. Clinicians should be meticulous when assessing the underlying pathology of the multifactorial causes of PML due to SLE. The difference in the transition pattern of these lesions on FLAIR images may be one of the characteristics of MRI findings in PML associated with SLE, reflecting fluctuations in disease activity and the progression stage of PML.

JCV granule cell neuronopathy: A rare case manifestation.

Granule cell neuronopathy (GCN) caused by John Cunningham virus (JCV) is a rare yet significant neurological complication, particularly in immunocompromised individuals such as those with AIDS. We present a case of a 34-year-old HIV-positive male exhibiting classical symptoms of cerebellar dysfunction. Magnetic resonance imaging revealed demyelination suggestive of progressive multifocal leukoencephalopathy (PML). Histopathological examination confirmed JCV-GCN, characterized by lytic infection of cerebellar granule cell neurons. Among the 41 reported cases of JCV-GCN, histopathological data were available for only 10 cases. Ours is the 11th case with available histopathology. This case underscores the importance of considering JCV infection in the differential diagnosis of progressive cerebellar syndromes in immunocompromised patients. Early recognition and diagnosis are crucial for appropriate management and prognosis.

Pathology for severe inflammatory PML with PD1/PD-L1 expression of favorable prognosis: What's a prognostic factor for PML-IRIS?

A 72-year-old woman with dermatomyositis (DM) developed neurological manifestation, and magnetic resonance imaging (MRI) revealed multiple T2/fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions predominantly in the deep white matter of the cerebral hemisphere. Punctate or linear contrast enhancement was observed surrounding the T1-hypointense area. Multiple T2/FLAIR-hyperintense lesions were aligned along with the corona radiata. Malignant lymphoma was first suspected, and a brain biopsy was performed. Pathological investigation suggested the provisional diagnosis of "suspicious of malignant lymphoma." Owing to emergent clinical conditions, high-dose methotrexate (MTX) therapy was conducted, and then T2/FLAIR-hyperintense lesions were dramatically reduced. However, the diagnosis of malignant lymphoma was concerning since multiplex PCR demonstrated clonal restriction of the Ig H gene for B cells and TCR beta genes for T cells. Histopathology revealed the infiltration of both CD4+ and CD8+ T cells, and the CD4+ /CD8+ ratio was 4.0. Moreover, prominent plasma cells were observed, in addition to CD20+ B cells. Atypical cells with enlarged nuclei were present, and they were not hematopoietic but found as glial cells. JC virus (JCV) infection was verified with both immunohistochemistry and in situ hybridization; the final diagnosis was progressive multifocal leukoencephalopathy (PML). The patient was treated with mefloquine and discharged. This case is informative in understanding the host anti-viral response. Variable inflammatory cells were observed, including CD4+ and CD8+ T cells, plasma cells, and a small amount of perivascular CD20+ B cells. PD-1 and PD-L1 expression was observed in lymphoid cells and macrophages, respectively. PML with inflammatory reactions was thought fatal, and autopsy cases of PML with immune reconstitution inflammatory syndrome (IRIS) demonstrated excessive infiltration of only CD8+ T cells. However, this case revealed infiltration of variable inflammatory cells, and a favorable prognosis would be expected under PD-1/PD-L1 immune-checkpoint regulation.

JC Polyomavirus Modifies the Expression of Human microRNAs in Progressive Multifocal Leukoencephalopathy Brain.

Progressive multifocal leukoencephalopathy (PML) is a severe neurological condition caused by reactivation of JC polyomavirus (JCPyV) in immunosuppression. Asymptomatic JCPyV persists in peripheral tissues. Upon reactivation, neurotropic rearrangements may emerge, and the virus gains access to the brain. To assess the mechanisms of PML pathogenesis, brain tissue material from PML patients was collected for small RNA sequencing. Upregulation of 8 microRNAs (miRNAs) in PML brain was validated using quantitative microRNA polymerase chain reaction (PCR). Bioinformatics tools were utilized to identify major associations of the upregulated miRNAs: neuroinflammation and blood-brain barrier disruption. The results indicate involvement of human miRNA regulation in PML pathogenesis.

Progressive multifocal leukoencephalopathy with a benign prognosis in an immunocompetent patient - A case report.

John Cunningham virus (JCV) is most commonly acquired in childhood and is often asymptomatic throughout life. However, in the case of primary or secondary immunosuppression, it is known to cause progressive multifocal leukoencephalopathy (PML) in the central nervous system. Hereby, we describe a rare case of PML in a patient without known factors of immunosuppression or use of immunomodulation. A 53-year-old female patient was presented with progressive left-side weakness and tremors in the left hand over a period of two months. The patient was diagnosed with PML based on history, examination, cerebrospinal fluid markers, histopathology, and brain magnetic resonance imaging at presentation. Despite detailed examination, nothing was found in the patient to cause an immunosuppressed state. Therapy was started with mirtazapine with significant neurological improvement.To our knowledge, PML in immunocompetent patient with bening prognosis is a very rare condition. There is also no effective treatment. Our case is a complicated example of this condition.

An autopsy case of progressive multifocal leukoencephalopathy with massive iron deposition in juxtacortical lesions.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by JC virus infection of oligodendrocytes. Little has been reported on iron deposits in patients with PML. Herein, we report a case of PML with massive iron deposition in the juxtacortical regions attaching white matter lesions in a 71-year-old woman who developed bilateral visual disturbance and progressive aphasia after 16 months of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone treatment for follicular lymphoma. Magnetic resonance imaging revealed white matter lesions in the left parietal and other lobes with massive iron deposition in the juxtacortical lesions. A PCR test for JC virus was positive, confirming the diagnosis of PML. Despite treatment with mefloquine and mirtazapine, the patient died six months later. At autopsy, demyelination was found dominantly in the left parietal lobe. Moreover, hemosiderin-laden macrophages and reactive astrocytes containing ferritin were abundant in the juxtacortical regions adjacent to the white matter lesions. This is a previously unreported case of PML after lymphoma, in which iron deposition was confirmed both radiologically and pathologically.

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor.

The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed and immunomodulated patients. Initial infection with JCPyV is common and the virus establishes a long-term persistent infection in the urogenital system of 50-70% of the human population worldwide. A major gap in the field is that we do not know how the virus traffics from the periphery to the brain to cause disease. Our recent discovery that human choroid plexus epithelial cells are fully susceptible to virus infection together with reports of JCPyV infection of choroid plexus in vivo has led us to hypothesize that the choroid plexus plays a fundamental role in this process. The choroid plexus is known to relay information between the blood and the brain by the release of extracellular vesicles. This is particularly important because human macroglia (oligodendrocytes and astrocytes), the major targets of virus infection in the central nervous system (CNS), do not express the known attachment receptors for the virus and do not bind virus in human tissue sections. In this report we show that JCPyV infected choroid plexus epithelial cells produce extracellular vesicles that contain JCPyV and readily transmit the infection to human glial cells. Transmission of the virus by extracellular vesicles is independent of the known virus attachment receptors and is not neutralized by antisera directed at the virus. We also show that extracellular vesicles containing virus are taken into target glial cells by both clathrin dependent endocytosis and macropinocytosis. Our data support the hypothesis that the choroid plexus plays a fundamental role in the dissemination of virus to brain parenchyma.

Changes in Brain Volumes Are Relevant during Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: Lessons from a Case Report.

This is a case report concerning a Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) with cerebellar localization and wakefulness disturbances. Awakening and clinical improvement dramatically occurred as soon as the immune reconstitution inflammatory syndrome (IRIS) took place, being it mild in nature and colocalizing with the PML lesion. In these ideal experimental conditions, we applied brain magnetic resonance imaging post-analysis in order to know changes in brain volumes underlying the pathological process over the infection period. White matter volume increased with a decrease in grey matter during IRIS. Conversely, we found a constant increase in cerebrospinal fluid volume throughout the duration of PML, suggesting a widespread abiotrophic effect, far from the lesion. Furthermore, brain parenchymal fraction significantly decreased as expected while the total brain volume remained stable at all times. Neurodegeneration is the main contributor to the steady disability in Natalizumab-associated PML. This process is thought to be widespread and inflammatory in nature as well as sustained by IRIS and humoral factors derived from the PML lesion.

[The phenomenon of pseudotumorous cross immunohistochemical reactivity of glia in progressive multifocal leukoencephalopathy]. / Fenomen psevdotumoroznoi perekrestnoi immunogistokhimicheskoi reaktivnosti glii pri progressiruyushchei mul'tifokal'noi leikoentsefalopatii.

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating brain damage caused by infection of oligodendrocytes and astrocytes with the lytic JC virus on the background of immunosuppression. A case report of PML with a tumor-like course is presented. Morphological diagnostics revealed non-specific staining of antibodies to Ki-67, p53, IDH1, NF and Vim in the nuclei of gliocytes affected by the JC virus. Histological examination and microscopic evaluation of the changes in the brain for the diagnosis of PML is a priority. The recommended intravital biopsy does not always help in clear verification of PML due to the limited volume of tissue fragments presented for research. For the correct interpretation of changes during an intravital pathological examination and verification of PML, it is important to take material during a stereotaxic biopsy, not only from the center, but from the edges and perifocal zone of the altered tissues for the possibility of a spatial histological assessment of the pathological process.

Teriflunomide Inhibits JCPyV Infection and Spread in Glial Cells and Choroid Plexus Epithelial Cells.

Several classes of immunomodulators are used for treating relapsing-remitting multiple sclerosis (RRMS). Most of these disease-modifying therapies, except teriflunomide, carry the risk of progressive multifocal leukoencephalopathy (PML), a severely debilitating, often fatal virus-induced demyelinating disease. Because teriflunomide has been shown to have antiviral activity against DNA viruses, we investigated whether treatment of cells with teriflunomide inhibits infection and spread of JC polyomavirus (JCPyV), the causative agent of PML. Treatment of choroid plexus epithelial cells and astrocytes with teriflunomide reduced JCPyV infection and spread. We also used droplet digital PCR to quantify JCPyV DNA associated with extracellular vesicles isolated from RRMS patients. We detected JCPyV DNA in all patients with confirmed PML diagnosis (n = 2), and in six natalizumab-treated (n = 12), two teriflunomide-treated (n = 7), and two nonimmunomodulated (n = 2) patients. Of the 21 patients, 12 (57%) had detectable JCPyV in either plasma or serum. CSF was uniformly negative for JCPyV. Isolation of extracellular vesicles did not increase the level of detection of JCPyV DNA versus bulk unprocessed biofluid. Overall, our study demonstrated an effect of teriflunomide inhibiting JCPyV infection and spread in glial and choroid plexus epithelial cells. Larger studies using patient samples are needed to correlate these in vitro findings with patient data.

Human iPS cell-derived astrocytes support efficient replication of progressive multifocal leukoencephalopathy-type JC polyomavirus.

JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system, in immunocompromised patients. Although PML used to be rare, recently the incidence of PML has risen due to an increase in immunosuppressive therapy. An in vitro JCPyV infection system could be used for anti-drug screening and investigation of tropism changes, but study of JCPyV in vitro has been limited due to the difficulty of efficiently propagating the virus in cultured cells. PML-type JCPyV efficiently propagates in primary human fetal and progenitor cell-derived astrocytes, but the preparation of cells from human fetuses is associated with severe ethical problems. In this study, human iPS cell-derived astrocytes were exposed to PML-type JCPyV. Infection, replication, and VP1 and T antigens of JCPyV were detected and confirmed in this culture. The non-coding control region (NCCR) of M1-IMRb was conserved in infected cells without point mutations. In addition, PML-type JCPyV genomic DNA in infected cells was detected as a single band of approximately 5.1 kbp, with no deletions. This is the first demonstration that human iPS cell-derived astrocytes efficiently support replication of PML-type JCPyV without production of defective interfering particles. These findings indicated that a culture system using human iPS cell-derived astrocyte would be useful for studies of PML, especially for screening anti-JCPyV drugs.

Expression of Bone Morphogenetic Proteins in Multiple Sclerosis Lesions.

Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the transforming growth factor-ß superfamily. In the adult brain, they modulate neurogenesis, favor astrogliogenesis, and inhibit oligodendrogenesis. Because BMPs may be involved in the failure of remyelination in multiple sclerosis (MS), we characterized the expression of BMP-2, BMP-4, BMP-5, and BMP-7; BMP type II receptor (BMPRII); and phosphorylated SMAD (pSMAD) 1/5/8 in lesions of MS and other demyelinating diseases. A total of 42 MS lesions, 12 acute ischemic lesions, 8 progressive multifocal leukoencephalopathy lesions, and 10 central nervous system areas from four nonneuropathological patients were included. Lesions were histologically classified according to the inflammatory activity. The expression of BMP-2, BMP-4, BMP-5, BMP-7, BMPRII, and pSMAD1/5/8 was quantified by immunostaining, and colocalization studies were performed. In MS lesions, astrocytes, microglia/macrophages, and neurons expressed BMP-2, BMP-4, BMP-5, and BMP-7; BMPRII; and pSMAD1/5/8. Oligodendrocytes expressed BMP-2 and BMP-7 and pSMAD1/5/8. The percentage of cells that expressed BMPs, BMPRII, and pSMAD1/5/8 correlated with the inflammatory activity of MS lesions, and changes in the percentage of positive cells were more relevant in MS than in other white matter-damaging diseases. These data indicate that BMPs are increased in active MS lesions, suggesting a possible role in MS pathogenesis.

Epilepsia partialis continua revealing idelalisib-associated PML-IRIS: clinical and pathological features.

Idelalisib, a selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is a newly approved second-line drug for patients with chronic lymphocytic leukemia. Recent clinical trials have suggested a possible association between idelalisib treatment and development of progressive multifocal leukoencephalopathy (PML) due to John Cunningham virus (JCV) reactivation. Nevertheless, clinical course and radiological and pathological features of idelalisib-induced PML still need to be clarified. We provide here the first clinicopathological description of idelalisib-associated PML in a patient who developed epilepsia partialis continua (EPC) as the first manifestation of the disease. Since EPC could present without electroencephalogram alterations, it is crucial to recognize the clinical features of this epileptic condition. EPC is characterized by the presence of repetitive, irregular, clonic jerking, often associated with hemiparesis and involvement of distal rather than proximal muscle groups. Moreover, we highlight the importance of brain biopsy in selected cases when there is a high clinical suspicion of PML, despite negative JCV testing in the cerebrospinal fluid. The pathological finding of prominent inflammatory infiltrate observed here was consistent with a diagnosis of immune reconstitution inflammatory syndrome (IRIS). IRIS is often associated with PML as a paradoxical worsening of clinical symptoms due to an overreacting immune response, in the context of previous immunosuppression. The unprecedented pathologic observation of IRIS in idelalisib-associated PML provides further insights into the pathogenesis of this rare neurological side effect.

Progressive multifocal leukoencephalopathy in an HIV patient was diagnosed by 3 times lumbar punctures and 2 times brain biopsies.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by JC virus (JCV) and is difficult to diagnose. We report on a male HIV-positive patient with PML finally diagnosed by 3 times lumbar punctures and 2 times brain biopsies. Negative results of JCV-PCR in cerebrospinal fluid (CSF) do not rule out the diagnosis of PML when clinical manifestations and neuroimaging features suspected PML. It is necessary to obtain new CSF and make repeat tests and even perform brain biopsy.

Pomalidomide-associated progressive multifocal leukoencephalopathy in multiple myeloma: cortical susceptibility-weighted imaging hypointense findings prior to clinical deterioration.

Although there are several case reports of progressive multifocal leukoencephalopathy (PML) in multiple myeloma (MM), there are few reports of cases associated with pomalidomide. Here, we report the case of a 69-year-old female who had received 41 cycles of pomalidomide and dexamethasone treatment for relapsed/refractory IgG-κ MM presented with right-hand weakness; she was diagnosed as pomalidomide-associated PML. Fluid-attenuated inversion recovery (FLAIR) on admission showed high signals in the bilateral front-parietal lobe white matter, with multiple punctate lesions in the vicinity of the main lesions. These punctate pattern findings on FLAIR were similar to that of natalizumab-associated PML. Susceptibility weighted imaging (SWI) showed hypointense rims within the cortex at unaffected sites, in the initial stages. Subsequently, the clinical manifestations deteriorated, and the FLAIR images showed new hyperintense white matter lesions at the sites where cortical SWI hypointense rims were detected on the initial MRI examination. Our patient's serial MRI findings suggest that cortical SWI hypointense rims appear prior to the visible demyelinating white matter lesions in patients with PML.

JCPyV NCCR analysis in PML patients with different risk factors: exploring common rearrangements as essential changes for neuropathogenesis.

BACKGROUND: During severe immunosuppression or treatment with specific biological drugs, human polyomavirus JC (JCPyV) may establish a lytic infection in oligodendrocytes, leading to progressive multifocal leukoencephalopathy (PML). Beyond AIDS, which represents the most common predisposing condition, several biological drugs have been associated to the development of PML, such as natalizumab, fingolimod and dimethyl fumarate, which have been showed to increase the risk of PML in the multiple sclerosis (MS) population. JCPyV non-coding control region (NCCR) can be found in two different forms: a virulent neurotropic pathogenic form and a latent non-pathogenic form. The neurotropic forms contain a rearranged NCCR and are typically found in the cerebrospinal fluid, brain or blood of PML patients. CASE PRESENTATION: We sequenced and critically examined JCPyV NCCR from isolates detected in the cerebrospinal fluid of four newly diagnosed progressive multifocal leukoencephalopathy patients: two HIV-positive and two HIV-negative multiple sclerosis patients. More complex NCCR rearrangements were observed in the two HIV-positive patients compared to the HIV-negative multiple sclerosis patients with PML. CONCLUSIONS: The comparison of HIV-positive and HIV-negative MS patients with PML, allowed us to evidence the presence of a common pattern of JCPyV NCCR rearrangement, characterized by the deletion of the D-block, which could be one of the initial rearrangements of JCPyV NCCR needed for the development of PML.

ERK Is a Critical Regulator of JC Polyomavirus Infection.

The human JC polyomavirus (JCPyV) infects the majority of the population worldwide and presents as an asymptomatic, persistent infection in the kidneys. In individuals who are immunocompromised, JCPyV can become reactivated and cause a lytic infection in the central nervous system resulting in the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML). Infection is initiated by interactions between the capsid protein viral protein 1 (VP1) and the α2,6-linked sialic acid on lactoseries tetrasaccharide c (LSTc), while JCPyV internalization is facilitated by 5-hydroxytryptamine 2 receptors (5-HT2Rs). The mechanisms by which the serotonin receptors mediate virus entry and the signaling cascades required to drive viral infection remain poorly understood. JCPyV was previously shown to induce phosphorylation of extracellular signal-regulated kinase (ERK), a downstream target of the mitogen-activated protein kinase (MAPK) pathway, upon virus entry. However, it remained unclear whether ERK activation was required for JCPyV infection. Both ERK-specific small interfering RNA (siRNA) and ERK inhibitor treatments resulted in significantly diminished JCPyV infection in both kidney and glial cells yet had no effect on the infectivity of the polyomavirus simian virus 40 (SV40). Experiments characterizing the role of ERK during steps in the viral life cycle indicate that ERK activation is required for viral transcription, as demonstrated by a significant reduction in production of large T antigen (TAg), a key viral protein associated with the initiation of viral transcription and viral replication. These findings delineate the role of the MAPK-ERK signaling pathway in JCPyV infection, elucidating how the virus reprograms the host cell to promote viral pathogenesis.IMPORTANCE Viral infection is dependent upon host cell factors, including the activation of cellular signaling pathways. These interactions between viruses and host cells are necessary for infection and play an important role in viral disease outcomes. The focus of this study was to determine how the human JC polyomavirus (JCPyV), a virus that resides in the kidney of the majority of the population and can cause the fatal, demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals, usurps a cellular signaling pathway to promote its own infectious life cycle. We demonstrated that the activation of extracellular signal-regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway, promotes JCPyV transcription, which is required for viral infection. Our findings demonstrate that the MAPK-ERK signaling pathway is a key determinant of JCPyV infection, elucidating new information regarding the signal reprogramming of host cells by a pathogenic virus.

Susceptibility of Primary Human Choroid Plexus Epithelial Cells and Meningeal Cells to Infection by JC Virus.

JC polyomavirus (JCPyV) establishes a lifelong persistence in roughly half the human population worldwide. The cells and tissues that harbor persistent virus in vivo are not known, but renal tubules and other urogenital epithelial cells are likely candidates as virus is shed in the urine of healthy individuals. In an immunosuppressed host, JCPyV can become reactivated and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system. Recent observations indicate that JCPyV may productively interact with cells in the choroid plexus and leptomeninges. To further study JCPyV infection in these cells, primary human choroid plexus epithelial cells and meningeal cells were challenged with virus, and their susceptibility to infection was compared to the human glial cell line, SVG-A. We found that JCPyV productively infects both choroid plexus epithelial cells and meningeal cells in vitro Competition with the soluble receptor fragment LSTc reduced virus infection in these cells. Treatment of cells with neuraminidase also inhibited both viral infection and binding. Treatment with the serotonin receptor antagonist, ritanserin, reduced infection in SVG-A and meningeal cells. We also compared the ability of wild-type and sialic acid-binding mutant pseudoviruses to transduce these cells. Wild-type pseudovirus readily transduced all three cell types, but pseudoviruses harboring mutations in the sialic acid-binding pocket of the virus failed to transduce the cells. These data establish a novel role for choroid plexus and meninges in harboring virus that likely contributes not only to meningoencephalopathies but also to PML.IMPORTANCE JCPyV infects greater than half the human population worldwide and causes central nervous system disease in patients with weakened immune systems. Several recent reports have found JCPyV in the choroid plexus and leptomeninges of patients with encephalitis. Due to their role in forming the blood-cerebrospinal fluid barrier, the choroid plexus and leptomeninges are also poised to play roles in virus invasion of brain parenchyma, where infection of macroglial cells leads to the development of progressive multifocal leukoencephalopathy, a severely debilitating and often fatal infection. In this paper we show for the first time that primary choroid plexus epithelial cells and meningeal cells are infected by JCPyV, lending support to the association of JCPyV with meningoencephalopathies. These data also suggest that JCPyV could use these cells as reservoirs for the subsequent invasion of brain parenchyma.

The "milky way" galaxy of HIV-related central nervous system immune reaction syndromes.

The landscape of central nervous system HIV infection is rapidly changing, leading to the recognition of a new constellation of overlapping syndromes and to a better insight for the elder ones. Among these, progressive multifocal leukoencephalopathy (PML) still poses several diagnostic and therapeutic challenges; nevertheless, recent developments in understanding PML in patients with multiple sclerosis may have benefitted HIV-positive patients suffering from PML too. We describe a peculiar case of PML-immune reconstitution inflammatory syndrome (IRIS) presenting a punctate pattern with "milky way" appearance on magnetic resonance imaging. Despite the fact that brain imaging and histopathology remain the mainstays for extricating through the expanding galaxy of HIV-related central nervous system dysimmune syndromes and although punctate pattern has been already well acknowledged as a suggestive finding of PML among patients on natalizumab, this radiological presentation is still poorly recognised in AIDS-related PML cases, leading to possible life-threatening diagnostic delays. This is also the first report about intravenous immunoglobulin treatment in AIDS-related PML-IRIS; the favourable clinical and radiological outcome of our case and the preliminary administrations of intravenous immunoglobulins in natalizumab-associated PML-IRIS from literature support probable benefits also among HIV-positive patients.