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PubMed1990

Severe encephalitis resulting from coinfections with HIV and JC virus.

We observed 3 cases of progressive multifocal leukoencephalopathy (PML) among frozen CNS samples obtained at autopsy from 102 adult AIDS patients. In 2 patients, PML was associated with severe HIV encephalitis. In those 2 cases, the areas of extensive JC-induced demyelination were massively infiltrated by HIV infected macrophages/microglial cells with evidence for localized increase of HIV encephalitis in PML lesions. Using immunohistochemistry and in situ hybridization, we demonstrated that each virus infects, in a latent or productive fashion, different CNS cell populations. Therefore, the extension of HIV encephalitis could not be related to an intracellular transactivation of 1 virus by the other. However, the results are consistent with dissemination of viral infection by the recruitment of HIV-infected macrophages to damaged areas of the brain. This phenomenon might be generalized to other pathogens that are frequently associated with HIV CNS infection. Early detection and treatment of opportunistic CNS lesions could be important to prevent extension of HIV encephalitis.

AIDS Dementia Complex↗

PubMed2006

Irisolidone, an isoflavone metabolite, represses JC virus gene expression via inhibition of Sp1 binding in human glial cells.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease that results from an oligodendrocyte infection caused by the JC virus. Therefore, inhibiting the expression of JC virus is important for preventing and/or treating PML. This study found that irisolidone, an isoflavone metabolite, significantly inhibited the JC virus expression in primary cultured human astrocytes and glial cell lines. Studies examining the underlying mechanism revealed that a mutation of the Sp1 binding site downstream of the TATA box (Sp1-II) dramatically diminished the inhibitory activity of irisolidone. In addition, an irisolidone treatment repressed Sp1 binding to Sp1-II site, which is important for the basal JC virus promoter activity. The results suggest that the inhibitory effect of irisolidone against the JC virus may be attributed at least in part to the suppression of Sp1 binding to the JC virus promoter region. Therefore, the inhibition of the JC virus expression by irisolidone might provide therapeutic potential for PML caused by the JC virus.

Base Sequence↗

PubMed2001

[Diagnostic problems of expansive intracranial process in HIV infected patients of the Bobo-Dioulasso Central Hospital (Burkina Faso)].

In HIV infection, cerebral focal lesions are relatively frequent and raise many kinds of diagnostic problems. In tropical practice, neuroradiology is scarcely available and necropsy is still not developed. Therefore, diagnosis of intracerebral masses among patients is not easily performed. We examined a total of 72 patients who presented over a 3-year period. Patients were allocated to presumed diagnostic categories of toxoplasma encephalitis (TE), primary central nervous system lymphoma (PCNSL) or progressive multifocal leukoencephalopathy (PML), based on clinical and therapeutic criteria. In an internal medicine ward, we examined 72 suspected cases of intracerebral masses in a sample of 43 males (60%) and 29 females (40%). The average age was 38 years with extremes ranging from 21 to 72 years. Because of diagnostic problems, the presumption of a TE has been retained in 54 cases (75% of the sample) owing to the efficiency of the treatment of antitoxoplasmic proof. As for the other intracerebral masses, despite insufficient diagnostic means, the assumption of PCNSL was made for 8 cases and PML for 6 cases on the basis of evolutional criteria. In 4 cases, no diagnosis could be retained because of insufficient diagnostic means and treatment failure. Since brain tomodensitometry and brain biopsy are not available, treatment of toxoplasmosis has to be systematically set up whenever there is a presumption of intracerebral masses among patients with HIV infection. It is only in case of failure of this treatment that other hypotheses can be contemplated, especially as they are not entirely reliable.

Adult↗

PubMed2006

JC virus chromogenic in situ hybridization in brain biopsies from patients with and without PML.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyoma virus. Electron microscopy and immunohistochemistry are the traditional methods of confirming the presence of the virus in brain biopsies from these patients. We studied the brain biopsies from 7 patients with PML and 6 patients without PML with chromogenic in situ hybridization (CISH) for the JC polyoma virus using a commercially available probe. The biopsies from the patients with the PML cases were proven to contain the JC polyoma virus by traditional and molecular methods. The CISH findings were compared with the known state of infection. All (7/7) of the biopsies from patients with PML were positive for the presence of polyoma virus by CISH, whereas the biopsies from patients without PML were uniformly negative. CISH seems to be a useful tool for the detection of the JC virus in brain biopsies from patients with PML, and is more accessible because a commercial probe is available.

Brain↗

PubMed1997

Activity of JC virus archetype and PML-type regulatory regions in glial cells.

Sequence variations are seen in the JC virus promoter/enhancer in virus taken from progressive multifocal leukoencephalopathy (PML) brains and it has been hypothesized that the variations arise in the host at some point in the development of PML. These rearrangements may be adaptations for enhanced growth in glial cells; if so, transcription or replication levels should differ between archetypal and rearranged PML-type promoters. The archetype and four PML-type promoters were analysed in human glial cells for early and late transcriptional activity in the absence or presence of virus T antigen, and for DNA replication. CAT reporter expression differed within a fivefold range and the archetype was intermediate in strength to the PML-type regulatory regions. The archetype differed from rearranged promoters in that the late promoter was less responsive to T antigen and the shift from early to late activity with T antigen was less pronounced. All five regulatory regions demonstrated similar levels of DNA replicating activity. Rearrangement of the archetype was not required for activity in glial cells, but the potential for differences in the regulation of the late capsid genes was found.

Antigens, Viral, Tumor↗

PubMed2004

Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals.

The polyomavirus JC (JCV) infects 85% of healthy individuals, and its reactivation in a limited number of immunosuppressed people causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system. We hypothesized that JCV-specific cytotoxic T lymphocytes (CTLs) might control JCV replication in healthy individuals, blocking the evolution of PML. Using 51Cr release and tetramer staining assays, we show that 8 of 11 HLA-A*0201+ healthy subjects (73%) harbor detectable JCV-specific CD8+ CTLs that recognize one or two epitopes of JCV VP1 protein, the HLA-A*0201-restricted VP1p36 and VPp1100 epitopes. We determined that the frequency of JCV VP1 epitope-specific CTLs varied from less than 1/100,000 to 1/2,494 peripheral blood mononuclear cells. More individuals had JCV VP1-specific than cytomegalovirus-specific CTLs (8 of 11 subjects [73%] versus 2 of 10 subjects [20%], respectively). These results show that a CD8+-T-cell response against JCV is commonly found in immunocompetent people and suggest that these cells might protect against the development of PML.

Adult↗

PubMed2025

Identification of Novel Wraparound Transcripts in JC Polyomavirus.

JC polyomavirus (JCPyV) is a ubiquitous pathogen that causes progressive multifocal leukoencephalopathy (PML). Although a recent study using next-generation sequencing (NGS) provided detailed transcriptome atlases for polyomaviruses (PyVs) such as BK polyomavirus and simian virus 40, the transcriptome of JCPyV remains poorly characterized. Here, we conducted a comprehensive analysis using both short-read and long-read NGS technologies to construct a transcriptome atlas of JCPyV. RNA extracted from IMR-32 and HEK293 cells transfected with the circular JCPyV genome was analyzed, leading to the identification of 39 previously uncharacterized viral transcripts in addition to 12 known ones. Among the novel transcripts, we identified wraparound transcripts, conserved across PyVs, which are generated through continuous, multicyclic transcription of the circular viral genome. These included both late transcripts containing leader-to-leader repeated sequences and SuperT transcripts with multiple LxCxE motifs. Notably, wraparound transcripts, including SuperT transcripts, were also detected in brain tissues from PML patients. Collectively, this study significantly expands our understanding of the JCPyV transcriptome, revealing the expression of wraparound transcripts in PML lesions. These findings provide valuable insights into the molecular basis of JCPyV gene expression and PML pathogenesis, potentially facilitating the development of effective countermeasures against PML.

JC Virus↗

PubMed2003

Increased 14-3-3 immunoreactivity in glial elements in patients with multiple sclerosis.

14-3-3 proteins have been shown to be increased in the cerebrospinal fluid from patients with several kinds of neurological diseases, including multiple sclerosis (MS). To investigate whether 14-3-3 proteins are closely related to the pathogenesis of MS, we performed immunohistochemical studies for 14-3-3 in autopsied brains from ten patients with MS, five patients with progressive multifocal leukoencephalopathy (PML), and seven normal control subjects. Formalin-fixed, paraffin-embedded sections from all cases were immunostained with a specific anti-14-3-3 antibody, and some sections from the MS cases were double-immunostained with antibodies raised against 14-3-3 and glial markers. In the normal control brains, 14-3-3 immunoreactivity was localized mainly in the neuronal somata and processes, and some glial cells showed only weak immunoreactivity. In the plaque lesions from the MS cases, the astrocytes and oligodendrocytes were intensely immunostained, and strong immunoreactivity was also found in some microglia and macrophages, most of which were located in the perivascular areas. In the PML brains, a similar immunolabeling pattern was observed in the demyelinated lesions, in which the astrocytes and oligodendrocytes exhibited dense 14-3-3 immunoreactivity. Our results suggest that 14-3-3 may be up-regulated in the glial cells, especially in astrocytes and oligodendrocytes, in patients with MS or PML. The exaggerated 14-3-3 accumulation in these glial elements may be associated with the pathogenesis of both demyelinating disorders.

14-3-3 Proteins↗

PubMed1998

Impact of opportunistic disease on survival in patients with HIV infection.

OBJECTIVE: To assess the impact of opportunistic diseases on survival in patients with HIV disease. METHODS: A cohort of 2081 patients followed for a mean of 30 months was studied. Time-dependent Cox proportional hazards analyses were performed using incident opportunistic diseases and CD4 cell counts as independent variables. RESULTS: During follow-up, 730 (35%) patients died. The occurrence of Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV) disease, Mycobacterium avium complex (MAC) disease, Candida esophagitis, Kaposi's sarcoma, lymphoma, progressive multifocal leukoencephalopathy (PML), dementia, wasting, toxoplasmosis, and cryptosporidiosis were all significantly associated with death, independently of CD4 cell count (all P<0.001 for opportunistic diseases controlling for CD4 cell count). The magnitude of increased risk was greatest for lymphoma [relative hazard (RH), 7.2], PML (RH, 3.9), MAC (RH, 3.0) and CMV (RH, 2.2). Cryptococcosis (RH, 0.94) and herpes zoster (RH, 0.85) were not associated with death. In a multivariate Cox proportional hazards analysis, MAC [RH, 2.56; 95% confidence interval (CI), 2.1-3.1], CMV (RH, 1.63; 95% CI, 1.3-2.1), toxoplasmosis (RH, 1.85; 95% CI, 1.3-2.6), PCP (RH, 1.29; 95% CI, 1.1-1.5), and CD4 cell count were significantly associated with death. Patients who had opportunistic diseases had significantly greatly monthly declines in CD4 counts (-11 x 10(6)/l per month) than those who did not (-6 x 10(6)/l per month; P <0.001). CONCLUSION: Most opportunistic diseases increase the risk of death independently of CD4 cell count. These data support the hypothesis that opportunistic diseases enhance HIV pathogenesis and further underscore the importance of prophylaxis.

AIDS Dementia Complex↗

PubMed1998

Prevalence of JC virus viraemia in HIV-infected patients with or without neurological disorders: a prospective study.

Progressive Multifocal Leukoencephalopathy (PML) is a severe demyelinating disease, which is rapidly fatal and is due to JC virus (JCV) infection, which especially occurs in HIV-infected patients. To investigate JCV pathophysiology and to evaluate the predictive value of JCV detection in blood, we looked for JCV DNA in leukocytes and plasma of 96 patients without any neurological symptoms and 109 patients with neurological diseases, among whom 19 were suffering from PML. JCV genome was detected in about 18% of all patients, i.e. 15.6% of patients with central nervous system disorders except PML, 13.5% of patients without neurological symptoms and significantly more often in PML patients (47.6%). Both leukocytes and plasma were tested; in plasma, JCV DNA was found in 36.1% of positive patients and in cells in 80.5%. Surprisingly in seven instances only the plasma contained JCV genome. One-year follow-up of these patients showed that the absence of JCV DNA in blood was associated with a very low probability of developing PML (negative predictive value=0.99).

Blotting, Southern↗

PubMed1997

Lack of evidence for the transmission of JC polyomavirus between human populations.

Human polyomavirus JC virus (JCV), the causative agent of progressive multifocal leukoencephalopathy, is ubiquitous in humans, infecting children asymptomatically then persisting in renal tissue. Since JCV DNA can readily be detected from urine, it should be a useful tool with which to study the mode of virus transmission in humans. Based on this notion, we examined the extent to which JCV was transmitted from the American to Japanese populations in Okinawa Island, Japan. (A population of about 50 000 American soldiers and families have been stationed in Okinawa since 1945.) Four JCV types (A to D) were identified in American populations in U.S.A., whereas only type B was prevalent in elder Japanese in Okinawa who had reached adulthood by 1945. Thus, types A, C, and D served as indicators of the transmission of JCV from American to Japanese populations. We then examined whether types A, C, and D were detectable in Japanese in Okinawa aged 30-50 years who may have been in contact with Americans during childhood. However, all the 125 isolates from the younger Japanese population were type B without exception. From this finding, we concluded that JCV is rarely transmitted between human populations.

Adult↗

PubMed1991

Sequence rearrangement in JC virus DNAs molecularly cloned from immunosuppressed renal transplant patients.

From nonimmunocompromised individuals, we have recently identified a possible archetypal JC virus DNA sequence from which various regulatory sequences of JC virus isolates derived from patients with progressive multifocal leukoencephalopathy (PML) could have evolved. In this study, we analyzed the regulatory sequences of JCV DNAs cloned from urine samples of a PML risk group (renal transplant patients on immunosuppressive therapy). A number of JC virus DNAs were molecularly cloned from virions excreted in the urine of eight patients. Furthermore, fragments containing the regulatory region were amplified by the polymerase chain reaction and subsequently molecularly cloned from cell-associated JC virus excreted in the urine of two patients. The regulatory regions in all clones were analyzed with restriction enzymes, and those in representative clones were sequenced. We found that clones with the archetypal regulatory sequence were predominant in all urine samples, but a few clones carried regulatory sequences that diverged from the archetypal sequence by deletion or duplication. The finding that sequence rearrangement in the archetypal regulatory region occurs in the course of infection in immunosuppressed hosts is consistent with the adaptation hypothesis which has been put forward to explain the divergence of the regulatory regions in PML-derived JC virus isolates.

Base Sequence↗

PubMed1983

Comparison of infectious JC virus DNAs cloned from human brain.

We cloned JC virus DNA obtained directly from brain tissue of 10 cases of progressive multifocal leukoencephalopathy and compared DNAs by restriction endonuclease mapping. Before cloning, each DNA preparation was homogeneous with respect to restriction patterns, but with the cloned DNAs we found variability in three regions of the genome among DNAs from different cases. There was a region of hypervariability between 0.67 and 0.725 map units; no two DNAs were exactly alike in this region. We determined that the origin of DNA replication also was in this region at 0.69 +/- 0.02 map units. In 4 of the 10 DNAs examined there was a deletion of approximately 75 base pairs between 0.14 and 0.235 map units, the region presumed to contain the codons for the C-terminal ends of the structural protein Vpl and for T antigen. JC virus DNA from these same four cases had an additional HincII-HpaI site at 0.895 map units in the presumptive Vp3 and Vp2 coding regions. Overall, no two JC virus genomes were identical although all were from fatal central nervous system infections and were infectious in vitro. Our restriction patterns suggest that there are two subtypes of JC virus circulating in the population.

Base Sequence↗

PubMed1984

Induction of brain tumors by a newly isolated JC virus (Tokyo-1 strain).

A newly isolated virus from a patient with progressive multifocal leukoencephalopathy (PML) (Tokyo-1 strain) was found serologically identical to JC virus (Mad-1 strain) and showed high neurooncogenicity in hamsters. Twenty-one animals inoculated intracerebrally with the virus developed brain tumors during a period that averaged 5 months. The tumors were cerebellar medulloblastoma (n = 20); plexus tumor (n = 2) occurred in 1 animal as a single tumor and in another in combination with a medulloblastoma. Thalamic gliomatosis was also present in 6 animals with medulloblastoma. Five mock-infected animals did not develop tumors. Medulloblastoma cells were shown to contain papovavirus T-antigen. In 20 animals examined the medulloblastoma showed a close resemblance to the human medulloblastoma in its histologic, immunocytochemical, and ultrastructural features. Examination of the incipient tumors indicated that the hamster medulloblastoma originated in cells in the neonatal external granular layer. Following infection the cells apparently migrated into the internal granular layer, carrying integrated virus genes and expressing phenotypical transformation. These findings confirm previous reports on the oncogenicity of virus isolates from PML (ZuRhein and Varakis, 1979), but are novel in that with this new isolate tumors could be induced with comparatively low levels of virus inocula.

Animals↗

PubMed2005

Detection of JC virus DNA sequences in brain tumors in pediatric patients.

OBJECT: The JC virus is a human neurotropic polyomavirus that causes progressive multifocal leukoencephalopathy and is closely related to simian virus 40. Several recent reports have indicated a possible association between the JC virus and the development of various human brain tumors. The authors examined the presence of JC virus DNA sequences in primary brain tumors in pediatric patients to evaluate the hypothesis that particular brain tumors can arise in the pediatric population as a consequence of infection with the JC virus. METHODS: Genomic DNA sequences were isolated from 62 brain tumors (32 medulloblastomas, 18 ependymomas, five choroid plexus papillomas, and seven pilocytic astrocytomas) and analyzed for the presence of JC virus DNA by Southern blot hybridization and direct sequencing. The JC virus DNA sequence was detected in five ependymomas and one choroid plexus papilloma. Immunohistochemical studies revealed nuclear expression of the large T-antigen in a choroid plexus papilloma. None of the medulloblastomas or pilocytic astrocytomas contained JC virus DNA. CONCLUSIONS: The results of this study provide molecular evidence of the association between JC virus and the development of certain ependymomas and choroid plexus papillomas.

Antigens, Viral, Tumor↗

PubMed1998

Oncogenic potential of human neurotropic papovavirus, JCV, in CNS.

The human polyomavirus, JCV, is the causative agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal human demyelinating disease. PML results from the cytolytic destruction of oligodendrocytes, the myelin-producing cells of the nervous system. JCV has also been shown to be tumorigenic in several animal models. Transgenic mice expressing the JCV early protein, T-antigen, develop poorly differentiated neural crest origin tumours. Intracerebral inoculation of JCV into newborn hamsters induces medulloblastomas, astrocytomas, and primitive neuroectodermal tumours. Further, inoculation of the virus into the brains of non-human primates, owl and squirrel monkeys, results in astrocytomas and glioblastoma multiforme. Several case reports have associated JCV with human CNS tumours in patients with concomitant PML, and one such report has detected JCV in a glial tumour in the absence of PML. The induction of neural origin tumours by JCV has been studied in transgenic mice harbouring the early genome of the virus. Alterations in the level and function of tumour suppressor proteins p53 and Rb, as well as associated cell cycle regulators, have been detected in tumour tissue from JCV T-antigen transgenic mice. Possible mechanisms by which JCV may exert its oncogenic potential by alteration of cellular growth control pathways in both humans and experimental animals are discussed.

Animals↗

PubMed1997

Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF.

OBJECTIVE: To identify disease patterns in AIDS-related focal brain lesions (FBL) and to design a decision-making strategy for differential diagnosis. DESIGN: Prospective study. Probabilities of CNS disorders were calculated using Bayes' theorem according to clinical variables (mass effect at CT or MRI, Toxoplasma serology, anti-Toxoplasma prophylaxis) and to the results of polymerase chain reaction (PCR) assays. PATIENTS: 136 consecutive HIV-infected patients with a definitive diagnosis of FBL-causing disorder observed from 1991 to 1995 in a single clinical setting. INTERVENTIONS: Patients underwent empiric anti-Toxoplasma therapy. After 3 weeks, patients with progressive/stable disease underwent brain biopsy. In 66 patients Epstein-Barr virus (EBV)-DNA, JC virus (JCV)-DNA, and T gondii-DNA amplification was performed by PCR in CSF. Diagnostic criteria were histopathologic examination of bioptic or autoptic tissue specimens for all disorders and complete/partial resolution of FBL after empiric therapy for toxoplasmic encephalitis (TE). RESULTS: Neuroradiologic characteristics did not discriminate between TE and primary CNS lymphoma (PCNSL). Probability of TE was 0.87 in Toxoplasma-seropositive patients with mass effect who were not receiving anti-Toxoplasma prophylaxis, but only 0.59 if prophylaxis was performed. In seronegative patients with mass effect, the likelihood of PCNSL was 0.74. If EBV-DNA or T gondii-DNA tests were positive, the probability of PCNSL or TE increased to more than 0.96. The absence of T gondii-DNA did not exclude the possibility of a TE diagnosis. Among FBL without mass effect, the probability of progressive multifocal leukoencephalopathy (PML) was 0.81; this increased to 0.99 if JCV-DNA testing was positive. Sensitivity of brain biopsy was 93%, with a perioperative morbidity of 12% and a mortality of 2%. CONCLUSIONS: Due to the low diagnostic capability of clinical variables, PCR amplifications in CSF, especially for EBV-DNA and for JCV-DNA, represent, in most cases, an essential step in the differential diagnosis of AIDS-related FBL. This is particularly true in patients with FBL without mass effect or with mass effect and who are either seronegative or undergoing anti-Toxoplasma prophylaxis. Brain biopsy remains a necessary procedure in EBV-DNA-positive cases and in seronegative patients with FBL displaying a mass effect. Positive JCV-DNA testing may obviate the need for brain biopsy in patients with FBL without mass effect. An advanced diagnostic strategy based on combined clinical criteria and PCR tests may allow rapid and accurate identification of patients for prompt brain biopsy or specific therapy.

AIDS Dementia Complex↗

PubMed1998

The human polyomavirus, JCV, and neurological diseases (review).

JC virus, a human neurotropic polyomavirus, is the established etiologic agent of the fatal demyelinating disease, progressive multifocal leukoencephalopathy, which usually affects individuals with defects in cell-mediated immunity. Cytolytic destruction of oligodendrocytes, the myelin-producing cells of the central nervous system is attributed as the mechanism by which JCV induces demyelination. PML was at one time a rare complication however it is now a much more common disease affecting patients of all ages due to the prevalence of AIDS. Of interest, in vitro evidence points to a cooperative interaction between JCV and HIV-1, via the HIV-1 regulatory protein, Tat. In addition, JCV has been demonstrated to induce tumors of neural origin in several animal models, including rodents and non-human primates, and several clinical reports have suggested a possible association between JCV and glial-origin tumors in humans. The viral regulatory protein, T-antigen, which has been shown to play a key role in orchestrating the events of the viral lytic cycle, is also capable of altering cellular functions, by nature of its direct interaction with cellular regulatory proteins and by its effect on cellular transcription. In this review, we discuss clinical aspects of PML, the ability of JCV to induce tumors in animal models, and the ability of JCV T-antigen to alter cellular function in vitro.

AIDS-Related Opportunistic Infections↗