JC Virus Infection Research Articles

JC polyomavirus, progressive multifocal leukoencephalopathy.

JC virus (JCV) is an ubiquitous human polyomavirus which causes persistent infections. The biological cycle of JCV in its host is incompletely known. Most infected individuals remain asymptomatic lifelong despite occasional viral urinary shedding. In some cases of immune depression, JCV may reactivate, gain access to the central nervous system, infect and harm glial cells involved in myelin production, leading to a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML). PML cases have recently increased in patients receiving monoclonal antibody therapies -in particular multiple sclerosis patients treated with natalizumab- raising a new interest in the pathophysiology of JCV infection. The tropism of JCV for glial cells has been associated with various mutations and rearrangements in the non-coding control region (NCCR) of JCV genome, a regulator of viral expression. Several hypotheses have taken into account this hypervariability to explain the pathogenesis of JCV infection.

A link between long-term natalizumab dosing in MS and PML: Putting the puzzle together.

When an infectious serious adverse event is linked with a therapy for an underlying disease, it usually is seen in a few weeks or months, not years. This is not the case with the effective monoclonal antibody therapy for patients with multiple sclerosis (MS) natalizumab (Tysabri), the α4 integrin inhibitor preventing inflammatory T cells entering the brain. The infectious adverse event in patients with MS is another demyelinating disease, progressive multifocal leukoencephalopathy (PML), caused by lytic infection of oligodendrocytes with JC virus (JCV), a ubiquitous agent in the population. Although cases of PML are seen in patients with MS after receiving as few as 7 monthly doses, the highest incidence of PML, 1/75 or higher,1 occurs after 24 monthly doses. Other risk factors for PML in these patients implicate prior exposure to JCV infection evidenced by presence of antiviral antibody as well as previous immunosuppressive treatments.2

Concomitant granule cell neuronopathy in patients with natalizumab-associated PML.

Granule cell neuronopathy (GCN) is a rare JC virus infection of the cerebellar granule cell neurons in immunocompromised patients. On brain imaging, GCN is characterized by cerebellar atrophy which can be accompanied by infratentorial white matter lesions. The objective of this study is to investigate the prevalence of MRI findings suggestive of GCN in a large natalizumab-associated progressive multifocal leukoencephalopathy (PML) cohort. MRI scans from before, at the time of, and during follow-up after diagnosis of PML in 44 natalizumab-treated MS patients, and a control group of 25 natalizumab-treated non-PML MS patients were retrospectively reviewed for imaging findings suggestive of GCN. To assess and quantify the degree of cerebellar atrophy, we used a 4 grade rating scale. Three patients in the PML group showed imaging findings suggestive of GCN and none in the control group. In two of these PML patients, cerebellar atrophy progressed from grade 0 at the time of diagnosis of isolated supratentorial PML to grade 1 and 2 after 2.5 and 3 months, respectively, in the absence of infratentorial white mater lesions. The third patient had grade 1 cerebellar atrophy before diagnosis of infra- and supratentorial PML, and showed progression of cerebellar atrophy to grade 2 in the 3 months following PML diagnosis. None of the other eight patients with infratentorial PML lesions developed cerebellar atrophy suggestive of GCN. Three cases with imaging findings suggestive of GCN were detected among 44 natalizumab-associated PML patients. GCN may, therefore, be more common than previously considered in natalizumab-associated PML patients.

Neuropathology of JC virus infection in progressive multifocal leukoencephalopathy in remission.

To investigate the neuropathology of the brain in a rare case of remission following diagnosis of progressive multifocal leukoencephalopathy (PML). Consent from the family for an autopsy was obtained, clinical records and radiograms were retrieved. A complete autopsy was performed, with brain examination after fixation and coronal sectioning at 1 cm intervals. Fourteen regions were collected for paraffin embedding and staining for microscopic analysis. Histologic sections were stained with Luxol blue, hematoxylin/eosin, and immunostained for myelin basic protein, neurofilament, SV40 T antigen and p53. The biopsy material was also retrieved and sections were stained with hematoxylin/eosin and immunostained for SV40 and p53. Sections were examined by American Board of Pathology certified pathologists and images captured digitally. Review of the clinical records was notable for a history of ulcerative colitis resulting in total colectomy in 1977 and a liver transplant in 1998 followed by immune-suppressive therapy. Neurological symptoms presented immediately, therefore a biopsy was obtained which was diagnosed as PML. Immunotherapy was adjusted and clinical improvement was noted. No subsequent progression was reported. Review of the biopsy demonstrated atypical astrocytes and enlarged hyperchromatic oligodendroglial cells consistent with JC virus infection. Strong SV40 and p53 staining was found in glial cells and regions of dense macrophage infiltration were present. On gross examination of the post-mortem brain, a lesion in the same site as the original biopsy in the cerebellum was identified but no other lesions in the brain were found. Microscopic analysis of this cerebellar lesion revealed a loss of myelin and axons, and evidence of axonal damage. This single burned-out lesion was equivocally positive for SV40 antigen with little p53 staining. Examination of thirteen other brain regions found no other occult sites. Our study reveals residual damage, rare macrophages or other inflammation and minimal evidence of persistent virus. This case demonstrates the possibility of complete remission of PML.

Progressive Multifocal Leukoencephalopathy with Balanced CD4/CD8 T-Cell Infiltration and Good Response to Mefloquine Treatment

A 53-year-old man was admitted for sub-acute progressive dementia and Gerstmann syndrome. MRI demonstrated lesions in the white matter involving the left parietal lobe, accompanied by speckled or faint linear peripheral enhancement. Brain biopsy revealed JC virus infection in oligodendrocytes and balanced infiltration of CD8+ and CD4+ T lymphocytes. We diagnosed progressive multifocal leukoencephalopathy (PML) with controlled inflammation. The finding of CD4/CD8 T cells in the infected PML brain suggested therapeutically valuable immune system involvement, which we decided to preserve by withholding corticosteroids. We treated the patient with risperidone, cytarabine and mefloquine to suppress virus replication, but not with the corticosteroid that is conventionally used in inflammatory PML cases. The patient was discharged three months after admission, and one year later, his score on the Mini-Mental State Examination had recovered to 26/30, from 5/30 on admission.

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: current treatment options and future perspectives.

Progressive multifocal leukoencephalopathy (PML) is a rare but debilitating and frequently fatal viral disease of the central nervous system, primarily affecting individuals with chronically and severely suppressed immune systems. The disease was relatively obscure until the outbreak of HIV/AIDS, when it presented as one of the more frequent opportunistic infections in this immune deficiency syndrome. It attracted additional attention from the medical and scientific community following the discovery of significant PML risk associated with natalizumab, a monoclonal antibody used for treatment of relapsing-remitting multiple sclerosis. This was followed by association of PML with other immunosuppressive or immunomodulating drugs. PML is currently untreatable disease with poor outcomes, so it is a significant concern when developing new immunotherapies. Current prophylaxis and treatment of PML are focused on immune reconstitution, restoration of immune responses to JC virus infection, and eventual suppression of immune reconstitution inflammatory syndrome. This approach was successful in reducing the incidence of PML and improved survival of PML patients with HIV infection. However, the outcome for the majority of PML patients, regardless of their medical history, is still relatively poor. There is a high unmet need for both prophylaxis and treatment of PML. The aim of this review is to discuss potential drug candidates for prophylaxis and treatment of PML with a critical review of previously conducted and completed PML treatment studies as well as to provide perspectives for future therapies.

Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area.

The availability of a growing number of immunomodulatory medications over the past few years has been associated with various JC virus (JCV)-associated brain syndromes in patients with autoimmune diseases, including multiple sclerosis, Crohn's disease, and psoriasis that had not been previously recognized as predisposing factors for progressive multifocal leukoencephalopathy. This review covers the three novel syndromes discovered in the last decade that are caused by JCV infection of neurons and meningeal cells. For more than 30 years, JCV was thought to exclusively infect oligodendrocytes and astrocytes in the white matter of the brain of immunosuppressed individuals. We now recognize that JCV-infected glial cells are frequently located at the gray-white matter junction or exclusively within the gray matter causing demyelination in the cortex. Mutations in JCV can trigger a change in tropism leading to involvement of other cell types, such as neurons and meningeal cells, causing clinically distinct entities. These new features of JCV infection provide challenges for clinicians taking care of affected patients and investigators studying the biology of this polyomavirus, its pathogenesis, and tropism. We hope that increasing awareness of these syndromes will lead to early diagnosis, and pave the way for new avenues of research to better understand all aspects of JCV pathogenesis and develop efficient therapies for our patients. However, we need to remain vigilant and open to the possibility that additional JC variants or yet unknown polyomaviruses may also be associated with neurological diseases.

B cells and progressive multifocal leukoencephalopathy: search for the missing link.

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain. PML classically occurs in patients with severe immunodepression, and cases have recently been linked to therapeutic monoclonal antibodies such as natalizumab and also rituximab, which depletes B cells. B cells appear to play a complex role in the pathogenesis of PML. They may act as a viral reservoir and as a vector for viral dissemination in the central nervous system. Anti-JCV antibody responses appear to have a limited effect on JCV replication in the brain. However, accumulating evidence suggests that B cells may considerably influence T cell responses through their cytokine secretion. This immunomodulatory function of B cells may play an important role in the control of JCV infection and in the pathogenesis of PML, including rituximab-induced PML.

JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration

JC virus (JCV) infection of glial cells can lead to progressive multifocal leukoencephalopathy (PML) in immunocompromised patients. A newly described phenotype of the infection is infection of neurons. This distinct clinical and radiological syndrome is named JCV granule cell neuronopathy, characterized by exclusive or predominant cerebellar atrophy. We report the clinical and radiological longitudinal findings of 5 HIV-infected patients referred to us between September 2004 and November 2011 who exhibited JCV granule cell neuronopathy (4 probable cases and 1 possible). The association of immunocompromised status, progressive cerebellar syndrome, MRI abnormalities with cortical cerebellar atrophy and cerebrospinal fluid positive for JCV on PCR allowed for a highly probable diagnosis. The reversal of the immunocompromised status is the only way to stop the disease evolution. Motor functioning can remain impaired, but the illness itself, unlike progressive multifocal leukoencephalopathy, does not seem to threaten life.

Progressive multifocal leukoencephalopathy: Dot-shaped inclusions and virus-host interactions.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by reactivation of the asymptomatic persistent pathogen human polyomavirus JC (JC virus). The pathology of affected brain tissues demonstrates oligodendroglia-like cells with viral inclusions in their enlarged nuclei, a diagnostic hallmark of this disease. Today, the pathological features of this disease are expanding, partly due to an unsteady balance between viral virulence and host immunity. Intranuclear viral inclusions were initially thought to be amphophilic materials comprising the entire enlarged nucleus, based on HE staining (full inclusions). Howevewr, recent immunohistochemical analyses detected the presence of intranuclear viral inclusions in dots (dot-shaped inclusions). The dot-shaped inclusions reflect clustered progeny virions at punctuated subnuclear domains called promyelocytic leukemia nuclear bodies, and are indicative of early-stage viral infection or suppressed viral proliferation. Second, the JC virus is usually reactivated in patients with impaired immunity, and therefore the inflammatory reactions are poor. However, the causes of immunosuppression are divergent, as seen with the frequent use of immunosuppressive drugs, including natalizumab. Therefore, the degree of host immunity is variable; some patients show marked anti-viral inflammatory reactions and a good prognosis, indicating that a strong resistance against viral infection remains. Recovery of the immune system may also induce paradoxical clinical worsening, known as immune reconstitution inflammatory syndrome, the mechanism of which has not been clarified. The virus-host interactions have increased in complexity, and the pathology of PML is diverging. In this review, the pathology of PML will be described, with a focus on the intranuclear target of JC virus infection and host inflammatory reactions.

Rituximab treatment did not aggravate ongoing progressive multifocal leukoencephalopathy in a patient with multiple sclerosis

A multiple sclerosis (MS) patient developed progressive multifocal leukoencephalopathy (PML) after 43months of natalizumab treatment. New clinical and magnetic resonance imaging (MRI) findings were initially misinterpreted as breakthrough MS disease activity and natalizumab treatment was replaced by rituximab treatment. The patient had a single infusion of rituximab 1000mg before a definite PML diagnosis was confirmed. Despite undetectable levels of B-cells, JC virus DNA became undetectable in the cerebrospinal fluid by quantitative polymerase chain reaction. The patient partially recovered without any clinical or MRI signs of new MS activity. These findings suggest that B-cell depletion in a non-immune compromised individual did not prevent the patient from clearing the JC virus infection.

Do polyomavirus hominis strains BK and JC play a role in oral squamous cell carcinoma?

Head and neck cancers are the most common cancers worldwide. It is estimated that approximately 90% of all head and neck cancers are represented by squamous cell carcinoma (SCC). There are many risk factors causing this type of cancer, including environmental factors and lifestyle choices, such as tobacco smoking or abusing alcohol. Other important risk factor include infectious factors. The aim of this study was to analyze the prevalence of BK and JC virus infections among patients with oral squamous cell carcinoma (OSCC). The correlation between BKV infection and OSCC, and correlation between BKV, OSCC, alcohol abuse, tobacco smoking, demographic data, pre-treatment staging, metastases of lymph node evidence, and grading, was analyzed. The study group consisted of 92 patients with squamous cell carcinoma (OSCC), 75 males, and 17 females, aged between 40 - 87 (average 56.8). All the patients underwent surgery and were not subjected to chemotherapy or radiotherapy prior to treatment. The analyzed samples were collected from paraffin sections. BKV DNA was detected in 18.5% of patients with OSCC. In the control group, BKV DNA was detected in 3.3%. BKV DNA was statistically more frequently detected among patients with squamous carcinoma, compared to the control group (p<0.05). The obtained results suggest that the BKV virus may play an important role in the development of oral squamous cell carcinoma.

Markers of JC virus infection in patients with multiple sclerosis under natalizumab therapy.

Objective:To evaluate the frequency of JC polyomavirus (JCPyV) infection and anti-JCPyV antibodies in patients with multiple sclerosis under natalizumab therapy.Methods:Presence of anti-JCPyV antibodies and JCPyV DNA was analyzed in 39 patients with relapsing-remitting multiple sclerosis undergoing natalizumab therapy. Anti-JCPyV antibodies were evaluated in serum by a 2-step virus-like particle-based ELISA assay (Stratify), and JCPyV DNA was evaluated in peripheral blood mononuclear cells, plasma, and urine by quantitative PCR. The anti-JCPyV antibodies were evaluated in serum samples collected at the same time or later than those collected for DNA analysis.Results:JCPyV DNA was detected in 59% of patients, and anti-JCPyV antibodies were present in 67%. JCPyV DNA occurred more often in blood than in urine. Anti-JCPyV antibodies were observed in 70% of the JCPyV-infected patients, and JCPyV DNA was detected in 50% of the patients without anti-JCPyV antibodies. When JCPyV DNA was investigated in blood and urine the frequency of infection was higher than previously described.Conclusion:Under these experimental conditions, with respect to the observed frequency of JCPyV infection, the sensitivity of the anti-JCPyV antibody assay was lower than expected.

Genetic variability of the VP1 gene of BK and JC polyomaviruses in HIV-infected patients

Human polyomaviruses, BK virus (BKV) and JC virus (JCV), are world widely distributed in human population. After primary infection, BKV and JCV establish latency in kidneys and upper part of urinary tract. In seropositive healthy individuals asymptomatic reactivation of both viruses occurs in in 0.5-20%. On the other hand, reactivation of these viruses in imunosuppressed patients, primarily in patients with T cell immunodeficiency, can lead to development of polyomavirus-associated diseases. Some of these diseases such as progressive multifocal leukoencephalopathy (PML), polyomavirus-induced nephropathy (PVN), hemorrhagic cystitis (HC) are life-threatening diseases with high mortality and morbidity rate. However, they do not affect all immunosuppressed patients, suggesting that other factors, such as genetic variability of BKV and JCV, can contribute to their occurrence. Immunosuppression leads to increased levels of replication of both viruses. Increased levels of replication are associated with higher incidence of mutations in the VP1 gene. Mutations, especially those located in outer loops, may lead to changed tropism and generation of more aggressive variants of BKV and JCV. This review is focused on clinical significance of BK and JC virus infection in immunosuppressed patients, especially in HIV-infected, and sequence changes in the VP1 gene that can contribute to selection of more virulent variants of BKV and JCV via adaptive evolution.

HIV-Associated JC Virus-Granule-Cell Neuronopathy (JCV-GCN) with the Hot-Cross-Bun Sign

Progressive multifocal leukoencephalopathy has long been described as the sole feature of JC virus (JCV) infection of the central nervous system. Over the past decade, its spectrum has extended to new forms of encephalopathy, notably affecting neurons. We describe an HIV-infected patient with worsening cerebellar symptoms, progressive cerebellar atrophy and a hot-cross-bun sign attributed to JCV–granule-cell neuronopathy (GCN), and 20 years of follow-up.

JC virus nucleotides 376-396 are critical for VP1 capsid protein expression.

JC virus (JCV) infection of the brain can cause progressive multifocal leukoencephalopathy, JCV granule cell neuronopathy, and JCV encephalopathy (JCVE). JCVCPN, isolated from the brain of a patient with JCVE, is a naturally occurring strain of JCV with a 143-base pair deletion in the agnogene. Cell culture studies of JCVCPN have shown that the loss of these nucleotides in the agnogene results in impaired expression of VP1 and infectious virion production. To better understand the role of this DNA sequence in JCV replication, we generated a series of deletions in the agnogene on the backbone of a virus which has a mutated agnoprotein start codon preventing agnoprotein expression. We found that deletion of nucleotides 376-396 results in decreased levels of viral DNA replication and a lack of VP1 expression. These results indicate that these nucleotides play a crucial role in JCV replication.

MicroRNA miR-J1-5p as a potential biomarker for JC virus infection in the gastrointestinal tract.

IntroductionJC virus (JCV), a human polyomavirus that causes progressive multifocal leukoencephalopathy (PML), has been linked to colorectal cancer (CRC). However, determination of JCV infection and its role in carcinogenesis has been challenging, highlighting the need for better diagnostic strategies for this virus. JCV-specific microRNAs (miRNAs) were identified and shown to negatively regulate oncogenic JCV T-Ag. Herein, we determined the pattern of JCV miRNA expression in clinical specimens from healthy subjects and CRC patients.Material and MethodsJCV miRNA expression was validated in CRC cell lines transfected with the JCV T-Ag. Results were confirmed using CRC tissues that were expressed T-Ag. Expression of JCV-specific miR-J1-5p was measured in fresh stool samples from healthy volunteers, and samples from fecal occult blood test kits from healthy subject, and patients with colorectal neoplasms.ResultsJCV miR-J1-5p was detected in JCV-transfected, but not vector-transfected, CRC cells, and was stable between cell passages. MiR-J1-5p was present in all six JCV T-Ag+ CRC samples. Surprisingly, JCV miRNA was detectable in all normal tissues, but the expression was much lower in CRC tissues. Similarly, miR-J1-5p expression was present in all fecal samples, but expression was lower in CRCs compared to controls or adenoma patients.ConclusionJC virus-specific miR-J1-5p miRNA is a potential biomarker for viral infection, and the lower expression in patients with colonic neoplasia highlights its biological role regulating oncogenic T-Ag expression in CRC.ImpactJCV-specific miRNA is a candidate for the development of a non-invasive screening test, as well as therapeutic intervention for JCV-associated diseases.

AB1132 Dilemmas about Rheumatology and Progressive Multifocal Leukoencephalopathy: A Survey of Knowledge, Attitudes, Practices and Educational Needs in Portuguese Rheumatologists

BackgroundProgressive multifocal leukoencephalopathy (PML) is a devastating opportunistic infection of the central nervous system, caused by JC virus. PML has classically occurred in immunosuppressed patients, however it has attracted the...

The Risk of Progressive Multifocal Leukoencephalopathy Under Biological Agents Used in the Treatment of Chronic Inflammatory Diseases

Biological agents such as monoclonal antibodies and soluble cytokine receptors have taken on an expanding role in the treatment of chronic immune mediated diseases. Progressive multifocal leukoencephalopathy (PML) is a rare central neurological disease caused by JC virus infection that has been described in the setting of conditions with severe impairment of immune surveillance, such as haematological malignancies, stem cell or solid organ transplantation and AIDS. This serious demyelinating disease has recently been described in patients receiving monoclonal antibodies for chronic inflammatory diseases such as multiple sclerosis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus or psoriasis. We review here the disease of PML, the different biological agents used in chronic inflammatory diseases that are associated with an increased risk of PML (natalizumab, rituximab, efalizumab and alemtuzumab), and the potential mechanisms that may explain the development of PML. Based on current knowledge of the biology of the JC virus and on the mechanisms of action of these biological agents, we discuss currently available tools that may be helpful in evaluating the risk of PML in this patient population.