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PubMed2004

Evidence for involvement of transforming growth factor beta1 signaling pathway in activation of JC virus in human immunodeficiency virus 1-associated progressive multifocal leukoencephalopathy.

CONTEXT: Progressive multifocal leukoencephalopathy is a fatal demyelinating disease of the central nervous system frequently seen in patients with impaired immune systems, particularly acquired immunodeficiency syndrome. JC virus (JCV), a human neurotropic polyomavirus, is the etiologic infectious agent of this disease. OBJECTIVE: The significantly higher incidence of progressive multifocal leukoencephalopathy in patients with acquired immunodeficiency syndrome than in patients with other immunosuppressive conditions suggests that molecular interactions between human immunodeficiency virus 1 and JCV, via the Tat protein, are responsible for the activation of the JCV enhancer/promoter and the development of progressive multifocal leukoencephalopathy. An indirect mechanism through activation of cytokines, such as transforming growth factor beta1 and Smads 3 and 4, may also be responsible for the enhancement of JCV gene expression. DESIGN: Immunohistochemical analysis in progressive multifocal leukoencephalopathy samples and chloramphenicol acetyl transferase assays on cell cultures were performed to corroborate this hypothesis. RESULTS: The JCV capsid protein VP-1 was found in the nuclei of oligodendrocytes and in the nuclei and cytoplasm of bizarre astrocytes. Human immunodeficiency virus proteins, including p24 and Tat, were detected in the cytoplasm of astrocytes. Tat, but not p24, was detected in oligodendrocytes, suggesting that extracellular Tat accumulates in the nuclei of oligodendrocytes, where JCV gene transcription takes place. High levels of transforming growth factor beta1 and Smads 3 and 4 were detected in JCV-infected oligodendrocytes. Results from in vitro studies confirm activation of the JCV early and late promoters by Smads 3 and 4. CONCLUSIONS: These observations support our model, suggesting that the induction of transforming growth factor beta1 by human immunodeficiency virus 1 Tat can stimulate its downstream factors, including Smads 3 and 4, which in turn augment transcription of the JCV promoter in glial cells.

Adult↗

PubMed1999

[Progressive multifocal leukoencephalopathy].

PATHOGENESIS: Progressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system caused by infection and reactivation of JC-virus. About 5% of all HIV-infected patients develop this fatal disease. Although pathogenesis is not completely understood, progressive multifocal leukoencephalopathy is thought to be a persistent infection. The kidneys, bone marrow, peripheral blood lymphocytes and the brain itself are candidates for latency sites of JC-virus. Loss of T-helper-cells in the course of HIV-infection or other immunosuppressive states result in reactivation of JC-virus. DIAGNOSIS: Progressive multifocal leukoencephalopathy can be diagnosed by focal neurological symptoms, radiographic signs in magnetic resonance imaging and detection of JC-virus in brain tissue or cerebrospinal fluid. TREATMENT: A specific therapy is not yet available or established. Highly active antiretroviral therapy (HAART) and cidofovir are promising and may prove useful in the near future.

AIDS-Related Opportunistic Infections↗

PubMed1992

Alpha-interferon therapy in a case of probable progressive multifocal leukoencephalopathy.

Probable progressive multifocal leukoencephalopathy (PML) was diagnosed on the basis of clinical picture and magnetic resonance imaging in a 63-year-old man with a complete remission of a non-Hodgkin's lymphoma. After the introduction of intramuscular alpha-interferon therapy, his neurological state and MRI findings showed a clear improvement. Eighteen months after the onset of first symptoms the patient has significantly recovered from both aphasia and motor impairment, and shows only a mild attentional deficit.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Use of cidofovir in progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating illness caused by the JC virus, a polyomavirus that occurs in 4-5% of HIV-positive patients. Mortality is high, and no useful therapy has been identified. Highly active antiretroviral therapy (HAART) has been reported to be effective in halting progression of the disease in some, but not all, patients. Cidofovir has been shown to be active against polyomaviruses. OBJECTIVE: To review data on the use of cidofovir to treat PML. DATA SOURCES: English-language case reports and clinical studies were located through a literature search (MEDLINE and AIDSLINE, 1995-July 2000). STUDY SELECTION AND DATA EXTRACTION: Relevant case reports and studies describing the use of cidofovir for PML were reviewed. DATA SYNTHESIS: Most case reports describing the use of cidofovir have shown that the drug is effective in the treatment of PML. Some patients were also receiving HAART concurrently; therefore, it is not clear which treatment modality had a greater impact on PML. However, cidofovir may be effective in patients whose disease has progressed despite HAART or who are-unable to tolerate these regimens. A pilot study of cidofovir for treating PML has completed enrollment, but preliminary results showed no benefit. CONCLUSIONS: Cidofovir may be the most reasonable treatment option for PML in HIV-infected individuals who fail to improve with HAART or who are unable to tolerate these regimens. Patients who receive cidofovir should be monitored for renal and ocular toxicity.

Antiviral Agents↗

PubMed1998

Neuro-ophthalmic findings in progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the central nervous system found in immunodeficient patients, most frequently now in those infected with HIV. It may represent the initial manifestation of HIV infection. Since the central visual pathways may be affected, a variety of neuro-ophthalmic signs and symptoms can manifest. We studied the clinical, radiographic and histopathological characteristics of patients with PML. METHODS: The charts of 13 patients in whom PML was diagnosed in the Neuro-AIDS clinic at the Montreal Neurological Institute between November 1987 and March 1995 were reviewed. The diagnosis of PML was established by characteristic clinical features together with typical computed tomographic or magnetic resonance imaging findings, such as nonenhancing low-density (on computed tomography) or hyperintense (on T2-weighted magnetic resonance imaging) white-matter lesions, without mass effect. Neuro-ophthalmic findings were based on clinical examination by an ophthalmologist, neuro-ophthalmologist or neurologist. Tissue for pathological examination was obtained by biopsy in one case and at postmortem study in a second case. RESULTS: The most common finding was homonymous hemianopia, in five patients (38%). Other features included nystagmus (in two patients), diplopia with cranial nerve palsy (in one) and cortical blindness (in one). One of the patients exhibited involvement of the brain stem, a site not usually affected by this demyelinating process. INTERPRETATION: The diagnosis of PML should be considered in immunocompromised patients with neuro-ophthalmic findings, particularly those with homonymous hemianopia.

AIDS Dementia Complex↗

PubMed2006

Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients. METHODS: We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI. RESULTS: Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000). CONCLUSIONS: A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.

Antibodies, Monoclonal↗

PubMed2005

Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) remains a frequent and life-threatening complication of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Although one-half of patients with this disease will survive, the outcome is unpredictable at diagnosis, and prognostic markers are needed. METHODS: JC virus (JCV) DNA levels were measured in cerebrospinal fluid (CSF) samples obtained from 61 HIV-infected patients with PML, including 38 patients who were treated with HAART and 23 patients who did not receive HAART, with use of real-time polymerase chain reaction. The diagnostic reliability of the assay was evaluated by comparing CSF findings with histopathological findings in patients with PML or other HIV-related diseases of the central nervous system. The prognostic value was assessed by comparing JCV DNA levels with survival and other patient variables. RESULTS: The assay had a diagnostic sensitivity of 76% and specificity of 100%. In the first CSF sample obtained after onset of PML symptoms, JCV DNA values ranged from undetectable to 7.71 log copies/mL (median, 3.64 log copies/mL). JCV DNA levels >3.64 log copies/mL correlated significantly with shorter survival and lower CD4+ cell counts in patients not receiving HAART. However, neither relationship was found in patients who were treated with HAART. The analysis of sequential CSF samples obtained from 24 patients demonstrated a marked decrease in JCV DNA levels over time in HAART-treated patients showing PML stabilization, but not in untreated or HAART-treated patients with progressively fatal disease. CONCLUSIONS: Measurement of JCV DNA levels in CSF samples may be a useful virological marker for management of PML in patients receiving HAART.

Adult↗

PubMed1997

Progressive multifocal leukoencephalopathy in HIV.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by infection of oligodendrocytes by JC virus. As patients with HIV survive longer with severe immunodeficiency, the incidence of PML is rising. Diagnosis is not always easy and the gold standard remains histological confirmation of the characteristic lesions of PML which requires a brain biopsy. This is considered too invasive by many clinicians and patients alike and detection of JC virus DNA in the cerebrospinal fluid (CSF) using polymerase chain reaction (PCR) is used as an alternative to biopsy. JC virus subtype detection in brain, CSF and blood leukocytes may offer further diagnostic and prognostic possibilities. The aetiology, clinical features and diagnostic problems of PML are reviewed. At present the outlook for patients with confirmed PML is poor and there is currently no effective treatment. However, novel approaches to treatment are under investigation and show some promise.

AIDS-Related Opportunistic Infections↗

PubMed2001

Immune response in progressive multifocal leukoencephalopathy: an overview.

Progressive multifocal leukoencephalopathy (PML) is a disease usually occurring in immunosuppressed patients. By far the most common underlying immunosuppressive illness is the acquired immune deficiency syndrome, accounting for about 85% of PML cases currently seen in clinical practice. PML may occur in patients with deficits in the humoral and/or cellular immune response such as lymphoproliferative diseases, myeloproliferative diseases, carcinomatous diseases and acquired immunodeficiency due to autoimmune diseases and immunosuppressive therapy. The humoral immune response in PML is indicative of a persistent, reactivated infection with a prominent immunoglobulin (lgG) G synthesis to virus protein 1 (VP1). An lgM synthesis in serum is rarely found. In about 76% of PML cases, an intrathecal humoral immune response to recombinant VP1 can be found as compared to only 3.2% in healthy controls. The detection of intrathecally synthesized lgG antibodies to VP1 can be used as an additional diagnostic test for the diagnosis of PML. The magnitude of the intrathecal humoral immune response appears to rise over time and may be associated with a decrease of viral load in cerebrospinal fluid (CSF) and possibly the central nervous system (CNS). Compared to healthy controls, proliferation of peripheral blood mononuclear cells (PBMC) is reduced in PML patients. Immunological studies suggest a general impairment of the Th1-type T-helper cell function of cell-mediated immunity. Furthermore, the appearance of JCV-specific cytotoxic T-lymphocytes appears to be associated with a favorable clinical outcome.

Antibody Formation↗

PubMed2004

New insights into progressive multifocal leukoencephalopathy.

PURPOSE OF REVIEW: Progressive multifocal leukoencephalopathy is a deadly demyelinating disease of the central nervous system, which occurs in immunosuppressed individuals. It is caused by a reactivation of the polyomavirus JC, which induces a lytic infection of oligodendrocytes. This review covers recent developments in the clinical and pathological presentations of progressive multifocal leukoencephalopathy, and advances in the understanding of JC virus biology. RECENT FINDINGS: The availability of highly active antiretroviral therapy has changed the clinical spectrum of progressive multifocal leukoencephalopathy in HIV-infected individuals; although the incidence has not diminished, mortality has decreased from 90% to approximately 50% during the first 3 months as a result of recovery of the immune system. More progressive multifocal leukoencephalopathy patients are now negative for JC virus in the cerebrospinal fluid by polymerase chain reaction, which calls for a new consensus terminology. Inflammatory forms of the disease are also becoming more frequent, and are associated with a strong cellular immune response mediated by JC virus-specific CD8 cytotoxic T lymphocytes, which are instrumental in preventing disease progression. SUMMARY: Advances in the understanding of JC virus biology have shed new light on the pathogenesis of progressive multifocal leukoencephalopathy, and on its possible role in cerebellar atrophy in HIV-infected individuals. Findings on the cellular immune response against the virus have direct implications for patient management, and may lead to new forms of immunotherapies for progressive multifocal leukoencephalopathy. An animal model of progressive multifocal leukoencephalopathy in non-human primates will facilitate the development of novel therapeutic strategies.

AIDS-Related Opportunistic Infections↗

PubMed1983

Slow virus diseases of the CNS. 1. Subacute sclerosing panencephalitis, progressive rubella panencephalitis, and progressive multifocal leukoencephalopathy.

Several slowly progressive diseases of the human CNS are now known to be caused by viruses. Subacute sclerosing panencephalitis (SSPE) is caused by a measles virus that may be sequestered in the cell rather than eradicated; the disease occurs between the ages of 4 and 20. Progressive rubella panencephalitis (PRP) is caused by a rubella virus that persists in the CNS; its onset is about a decade after rubella-virus infection. Progressive multifocal leukoencephalopathy (PML) is caused by a papovavirus that lyses oligodendrocytes; it usually occurs between the ages of 50 and 60. All three disorders are characterized by usually slow mental and motor deterioration; patients with SSPE and PRP also have myoclonic seizures. The pathogenesis of these diseases is not yet understood, and there is no effective treatment. Death occurs within months to years.

Adolescent↗

PubMed1981

Progressive multifocal leukoencephalopathy.

Three cases of progressive multifocal leukoencephalopathy have occurred in one hospital in a 3-year period. The 3 patients had been receiving chemotherapy for chronic myeloid leukaemia, lymphocytic lymphoma and acute myeloid leukaemia respectively, and developed progressive neurological illnesses which resulted in their deaths. The routine neurological investigations were unhelpful and although the diagnosis was suspected in 2 cases, treatment was not given. It is felt that the disease is not as rare as originally believed and that brain biopsy should be more readily considered since progressive multifocal leukoencephalopathy is potentially treatable.

Astrocytes↗

PubMed2002

Multifocal progressive leukoencephalopathy occurring after refractory anemia and multiple infectious disorders consecutive to severe lymphopenia.

Progressive multifocal leukoencephalopathy (PML) is related to central nervous system infection with JC virus (JCV). This leukoencephalopathy occurs in immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS) or lymphoid malignancies. We describe here a patient with myelodysplastic syndrome who developed several life-threatening infections including listeriosis, tuberculosis, and PML. Listeriosis and recurrence of tuberculosis preceded the occurrence of PML. Neurologic features associated with major ataxia, speech disorders, and PML were documented by cranial magnetic resonance imaging showing typical features in the cerebellum and proven by polymerase chain reaction (PCR) detection of JCV DNA in the cerebrospinal fluid. No specific treatment was decided because of progression toward acute myeloid leukemia. In this case, PML occurred with no susceptibility and without immunosuppressive treatment. Our case adds further support to the association between the impairment of T-cell immune responses and myelodysplastic disorders.

Anemia, Refractory↗

PubMed1994

Progressive multifocal leukoencephalopathy complicating Wiskott-Aldrich syndrome. Report of a case and review of the literature of progressive multifocal leukoencephalopathy with other inherited immunodeficiency states.

OBJECTIVE: To describe the occurrence of progressive multifocal leukoencephalopathy (PML) in association with Wiskott-Aldrich syndrome, an X-linked recessive disorder with impairment of both cellular and humoral immunity. DESIGN: A detailed analysis of this patient's clinical illness, immunologic factors, neuroradiographic findings, and brain histopathologic conditions was undertaken. The medical literature on PML complicating congenital immunodeficient states was also reviewed. SETTING: A 1500-bed, university-affiliated, public health hospital. PATIENT: A 15-year-old boy with Wiskott-Aldrich syndrome. His neurologic illness was heralded by dysarthria and right-sided weakness and the diagnosis was established by brain biopsy specimen. Survival from the time of onset of PML was 10 months. CONCLUSION: Although PML typically occurs in the setting of severe acquired cellular immunodeficiency, often as a consequence of acquired immunodeficiency syndrome, organ transplantation, and leukemia and lymphoma, it may rarely accompany inherited immunodeficiency syndromes. The reported childhood cases of PML include three patients, aged 5, 11, and 18 years, with other inherited immunodeficiency syndromes. This patient represents the first time (to our knowledge) that PML has been reported to occur in association with Wiskott-Aldrich syndrome.

Adolescent↗

PubMed2025

Molecular characterization of JC virus in progressive multifocal leukoencephalopathy cases from India.

Progressive Multifocal Leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system caused by reactivation of the John Cunningham virus (JCV) in immunocompromised individuals. Despite an estimated 2.4 million people living with HIV in India, the reported incidence of PML remains lower than in Western countries, likely due to underdiagnosis, underreporting, and distinct host genetic and viral factors. The rising number of individuals on immunosuppressive therapies, including organ transplant recipients and those with autoimmune disorders, further emphasizes the need to study JC virus diversity in the Indian context. This study aimed to characterize the genetic diversity of JCV in India by sequencing the VP1 and non-coding control region (NCCR) from cerebrospinal fluid (n=30) of confirmed PML cases using Sanger sequencing. VP1 sequencing (n=23) revealed a predominance of genotypes 2 (subtypes 2D, 2A, 2B) and 3A. NCCR analysis (n=17) showed extensive rearrangements relative to the archetype form, with most sequences classified as Type II-R. Structural variations, including deletions, duplications, and insertions were common, particularly in blocks D, C, and F. Transcription factor binding sites (TFBS) were identified for TATA box, Tst-1, SP-1, p53, CEBPB, AP-1, NF-1, EGR-1, GF-1, CRE-TAR and NFkB. Additional TFBS were created due to rearrangements, often spanning two blocks. These findings underscore the genomic diversity of JCV in India and highlight the need for continued molecular surveillance to better understand its implications for high-risk populations.

Leukoencephalopathy, Progressive Multifocal↗

PubMed1997

[Progressive multifocal leukoencephalopathy: virological and neuropathological aspects].

Progressive multifocal leukoencephalopathy is a subacute demyelinating disease of the central nervous system due to an opportunistic infection by a polyomavirus, most often JC virus, which predominantly infects oligodendrocytes. Progressive multifocal leukoencephalopathy used to be a rare condition, usually complicating lymphoproliferative diseases. Since the onset of the AIDS epidemic, its incidence has considerably increased and HIV infection has become, by far, the main risk factor for the disease. In AIDS patients, progressive leukoencephalopathy frequently shows atypical clinical and pathological features. The development of malignant glial tumors, within demyelinating regions, in patients with progressive multifocal leukoencephalopathy, has been reported in exceptional cases. The course of progressive multifocal leukoencephalopathy is invariably fatal. The diagnosis can only be made with certainty by histopathological examination of the brain, on cerebral biopsy or at postmortem. However, neuroradiological features may be extremely suggestive in many cases and PCR seems to be a reliable technique for demonstrating viral genome in the CSF. A few antiviral treatments have been proposed, however their efficacy is difficult to assess due to the low prevalence of the disease and the occurrence of rare cases with spontaneously prolonged survival.

AIDS-Related Opportunistic Infections↗

PubMed1977

Diagnosis of progressive multifocal leukoencephalopathy by computed tomography.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system which predominantly affects immunologically compromised hosts. The distinctive CT appearance in three documented cases includes low-density lesions of central and convolutional white matter with scalloped lateral borders. Lesions demonstrate no mass effect or contrast material enhancement. Findings are discussed with reference to other entities which may produce a similar CT appearance.

Adult↗

PubMed1983

[Lasting focal signs in 2 cases of progressive multifocal leukoencephalopathy].

Two cases of progressive multifocal leukoencephalopathy, which occurred without a clinical setting of immune deficiency and developed as a unifocal brain lesion during 14 and 4 months, are reported. The diagnosis was established only by post mortem study in the first case and after five months by a brain biopsy in the second one. The difficulties of an early diagnosis in such cases should be now reduced with CT scan which may show a relatively specific picture, even when there is only one visible lesion.

Female↗