PML Patients Research Articles

2311. Long-term prognosis and risk factors for overall mortality in patients with progressive multifocal leukoencephalopathy

Abstract Background Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of JC virus, almost in patients with immunosuppressive conditions. PML is a fatal infection with a reported 3-month mortality rate of 30–50% and a 2-month mortality rate of up to 90% in the non-human immunodeficiency virus (HIV) population. Despite high mortality, studies on PML are still lacking due to its low prevalence and incidence. Therefore, this study aimed to figure out long-term prognosis of PML and prognostic factors for mortality through a long observation period. Methods We retrospectively reviewed 68 PML patients with admitted to two tertiary hospitals in South Korea from 1999 to 2021. A total of 47 PML patients were finally enrolled after exclusion. The primary endpoint was long-term overall mortality. For survival analysis, Kaplan-Meier curve and Cox proportional hazards model were used. Each patient was followed up until death or until the end of the study period, whichever came first. Results The median follow-up duration was 20 (interquartile range [IQR], 3–79) months. The median age was 46 years, 27 (57.4%) were diagnosed with HIV, 19 (40.4%) were using immunosuppressive drugs. The median last follow-up modified Rankin Scale (mRS) was higher in non-HIV PML patients group (5 [IQR, 4–6] vs 4 [IQR, 2–5], p=0.020). The median survival duration was 184 (IQR 74–1,566) days in the non-HIV group and 1,564 (IQR 254–3,444) days in the HIV group. The overall mortality rate of PML patients was significantly higher in non-HIV group (80.0% vs 40.7%, p=0.007), also confirmed by the Kaplan-Meier curve and log-rank test (p=0.007). Initial mRS (HR 1.685, 95% CI: 1.028–2.762, p=0.038), HIV patients with highly active antiretroviral therapy (HAART) (HR 0.374, 95% CI: 0.172–0.815, p=0.013) had a significant effect on overall mortality. Conclusion With the widespread adoption of HAART, the survival duration of HIV patients with PML has been extended, but the mortality rate is still high. Also, the prognosis for PML in non-HIV patients is still frustrated. Initial mRS is a significant risk factor for long-term overall mortality in PML patients. Early detection of PML and early initiation of HAART in HIV patients may improve the patient's prognosis. Disclosures All Authors: No reported disclosures.

The oncogenic roles of JC polyomavirus in cancer.

JC polyomavirus (JCPyV) belongs to the human polyomavirus family. Based on alternative splicing, the early region encodes the large and small T antigens, while the late region encodes the capsid structural proteins (VP1, VP2, and VP3) and the agnoprotein. The regulatory transcription factors for JCPyV include Sp1, TCF-4, DDX1, YB-1, LCP-1, Purα, GF-1, and NF-1. JCPyV enters tonsillar tissue through the intake of raw sewage, inhalation of air droplets, or parent-to-child transmission. It persists quiescently in lymphoid and renal tissues during latency. Both TGF-β1 and TNF-α stimulates JCPyV multiplication, while interferon-γ suppresses the process. The distinct distribution of caspid receptors (α-2, 6-linked sialic acid, non-sialylated glycosaminoglycans, and serotonin) determines the infection capabilities of JCPyV virions, and JCPyV entry is mediated by clathrin-mediated endocytosis. In permissive cells, JCPyV undergoes lytic proliferation and causes progressive multifocal leukoencephalopathy, while its DNA is inserted into genomic DNA and leads to carcinogenesis in non-permissive cells. T antigen targets p53, β-catenin, IRS, Rb, TGF-β1, PI3K/Akt and AMPK signal pathways in cancer cells. Intracranial injection of T antigen into animals results in neural tumors, and transgenic mice develop neural tumors, lens tumor, breast cancer, gastric, Vater’s, colorectal and pancreatic cancers, insulinoma, and hepatocellular carcinoma. Additionally, JCPyV DNA and its encoded products can be detected in the brain tissues of PML patients and brain, oral, esophageal, gastric, colorectal, breast, cervical, pancreatic, and hepatocellular cancer tissues. Therefore, JCPyV might represent an etiological risk factor for carcinogenesis and should be evaluated for early prevention, diagnosis, and treatment of cancers.

Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy.

ObjectiveProgressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)‐specific T cell therapy in a cohort of hematological patients with PML.MethodsBetween 2014 and 2019, 9 patients with a diagnosis of “definite PML” according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV‐specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen‐derived peptides.ResultsNone of the patients experienced treatment‐related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV‐specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow‐up.InterpretationAmong other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769–779

Cerebrospinal fluid analysis in 108 patients with progressive multifocal leukoencephalopathy

BackgroundProgressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically.MethodsWe analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups.ResultsThe PML group showed an elevated cell count (p < 0.001) compared to the control group, however, this effect was mainly driven by HIV-PML patients. This subgroup also demonstrated a significantly higher proportion of patients with a disturbed blood-CSF-barrier function.ConclusionsThis comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.

Virus-Specific T Cells (VSTs) Therapy for Progressive Multifocal Leukoencephalopathy (PML)- a Novel Therapy to Combat a Fatal Disease

<h3>Introduction</h3> PML is a rare infection with JC virus affecting mostly oligodendrocytes and the white matter of the central nervous system. It affects patients with profound cellular immunodeficiency such as uncontrolled HIV or those receiving immunosuppression for neoplastic and autoimmune diseases. Prognosis is poor as there is no effective therapy except for immune recovery which is not feasible in all cases. Herein, we describe using Quadrivalent (CMV,EBV, Adenovirus and BK) VSTs in a recipient of an unrelated donor hematopoietic cell transplant (HCT) with PML. <h3>Methods</h3> A 64-year-old female with history of acute myeloid leukemia who underwent 10/10 HLA matched unrelated donor peripheral blood HCT complicated by acute mild skin graft vs host disease. She was off all immunosuppression by 7 months post transplant. At 15 months post HCT, she presented with mild confusion, left hemianopia and difficulty performing some routine tasks. Brain MRI showed demyelination involving the right parietal lobe, corpus callosum and bilateral dorsal periventricular areas. <i>Cerebrospinal fluid (</i>CSF) with JC virus DNA load of 389,773 copies/ml. Serum JC virus level was 1112 copies/ml and CD 4 218 (8.7%). Patient was referred to Cincinnati Children's Hospital for third-party VST infusion . A 3/10 HLA matched unit from their existing VST bank was infused 3 days after her PML diagnosis. She received a total of 6 VST infusions, each 28 days apart. <h3>Results</h3> Patient was monitored with monthly <i>C</i>SF JC virus and weekly serum JC virus levels. JC virus was cleared from serum and CSF after the fourth and fifth VST infusions, respectively (figure 1). T cell expansion analysis against BK was done by ELISpot (figure 2). Patient received a total of 6 VST infusions. Neuro symptoms stabilized after the second infusion. At 7.5 months from diagnosis (3 months since last VST infusion), she remained neurologically stable with no new deficits, GVHD or other toxicities. <h3>Conclusions</h3> VSTs with BK activity is a promising therapy for PML patients in whom immune reconstitution is unlikely to occur in a short time frame. More studies are warranted to evaluate the efficacy and long term outcomes of this method. Physicians should be aware of this novel therapy in selected PML cases given poor disease outcomes and lack of effective alternative therapies.

High risk PML patients switching from natalizumab to alemtuzumab (P2.407)

High risk PML patients switching from natalizumab to alemtuzumab (P2.407)

High-Risk PML Patients Switching from Natalizumab to Alemtuzumab: an Observational Study.

IntroductionThe choice of therapy in patients withdrawing from natalizumab treatment is still an open question and neurologists need strategies to manage this group of patients. The aim of this study is to evaluate if alemtuzumab is able to control the disease when used in patient who have stopped natalizumab.Methods16 patients stopped natalizumab treatment after a median number of 20 infusions (range 12–114); all the patients were responders to natalizumab (neither clinical nor radiological activity during natalizumab therapy) and the reason for stopping was the risk of PML for all of them. Patients were switched to alemtuzumab after a median wash-out period of 70 days (range 41–99 days); patients underwent brain MRI every three months during natalizumab treatment and then just before starting alemtuzumab in order to exclude signs suggestive of PML; then, contrast-enhanced brain MRI was planned 6 and 12 months after alemtuzumab infusion.ResultsAt present, 8 out of 16 patients have a follow-up >6 months and 2 out of 8 reached 1-year follow-up; 5 have a follow-up of 3–6 months and 3 have a follow-up <3 months. Brain MRI at 6 months after alemtuzumab is available for 8 out of 16 patients and in all of them, neither signs of disease activity nor new lesions are present; in 2 out of 8 patients, brain MRI at 12 months is also available, showing no sign of disease activity. Clinical evaluation performed at 6 and at 12 months (when available) showed stability, in particular neither relapses nor increase in EDSS were observed.ConclusionsAlemtuzumab was able to control the disease course in patients who stopped natalizumab; of course, as this is a single-centre study and the number of patients is small, these findings are very preliminary and need further confirmation.

Incidence and prognosis of immune reconstitution inflammatory syndrome in HIV-associated progressive multifocal leucoencephalopathy.

Progressive multifocal leucoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) is the paradoxical worsening or unmasking of preexisting infection with JC virus attributable to a rapid recovery of the immune system after highly active antiretroviral therapy (HAART) initiation. We investigated the incidence and factors associated with PML-IRIS in HIV-infected patients. We also studied its influence on mortality of PML and the effect of corticosteroid therapy. Single-center retrospective analysis of HIV-infected patients diagnosed with PML from 1996 to 2012 who received HAART. Among 59 PML patients treated with HAART, 18 (30.51%) developed PML-IRIS (five delayed PML-IRIS, 13 simultaneous PML-IRIS). Patients who developed IRIS had lower CD4 counts prior to treatment (102 vs. 68.5, P < 0.05) and experienced a greater decline in HIV-RNA levels in response to HAART (2.5log vs. 2.95log, P < 0.05). Gadolinium enhancement on MRI was observed in 31.25% of PML-IRIS cases versus 2.56% of PML non-IRIS (P < 0.01). Survival rates were higher in patients with PML-IRIS compared to those with PML non-IRIS. Eight patients received corticosteroids, five of which had a good outcome. Patients who died were severely ill when treatment was initiated whereas patients who survived were treated before major neurological deterioration occurred. Nearly one-third of HIV-infected patients with PML develop IRIS after initiating HAART. Patients severely immunocompromised who experience a rapid virological response to HAART have a higher risk for PML-IRIS. There was a trend for lower mortality in patients with IRIS. Early treatment with corticosteroids might be useful.

Outcomes Following Allogeneic Stem Cell Transplantation (AlloSCT) in Patients with Primary Mediastinal (PMBL), Germinal Center B (GCB) and Non-GCB Cell-like Diffuse Large B Cell Lymphomas (DLBCL)

Background: Primary mediastinal (PMBL), GCB and non-GCB B-cell lymphoma are three major subtypes of DLBCL with distinct clinical outcomes. PMBL and DLBCL of GCB immunophenotype have a higher chance of cure than patients with non-GCB DLBCL when treated with conventional chemotherapy. In the relapsed/refractory setting, there is paucity of data regarding the impact of histological classification of DLBCL on survival following alloSCT in patients who were not eligible for or who have failed a prior autologous SCT (ASCT). Herein, we compare outcomes of alloSCT in these patients.Methods and Patients: We identified 101 de novo DLBCL patients who were treated at our center from January 1, 1998 to December 31, 2011. Seventeen (17%) tumors were PMBL. We determined the cell-of-origin in the remaining patients, based upon the Visco/Young and Choi immunohistochemical algorithms, and classified 62 (61%) as GCB and 22 (22%) as non-GCB tumors. GCB patients were older than non-GCB [median (range): 54 (21-70) vs 48(24-58) years, p=0.003)] and PMBL [26(19-48), P <0.001)]. Patients with PMBL, however, were more likely to have bulky disease at study entry (SE) than other subtypes [24% (PMBL) vs 5% (GCB) and 5% (non-GCB); P= 0.04]. Stage III-IV at SE in GCB, non-GCB and PMBL was present in 42%, 45% (P=0.8) and 35% (P=0.6), respectively; the number of prior chemotherapies received was 4 in both GCB and non-GCB and 5 in PMBL (P=0.3). The proportion of patients who have failed a prior ASCT was comparable in all three groups (32%, 32% and 47%, P=0.2). Refractory disease was present in 35% of GCB and PMBL patients at SE compared to 14% in non-GCB patients (P=0.03). Distribution of IPI, LDH, and proportion of PET+ patients (47%, 45% and 47%) were not statistically different in all 3 groups. A larger proportion of GCB patients (44%, reference) received non-myeloablative conditioning than non-GCB (23%, P=0.07), or PMBL (12%, P=0.3); the remaining patients received reduced-intensity conditioning (RIC). The proportion of patients who received a matched sibling donor in GCB, non-GCB and PML were 69% (reference), 64% (P=0.6) and 41% (P=0.03), respectively. The remaining patients received matched unrelated donors. More GCB patients received peripheral blood as stem cell source than non-GCB (89% vs 73%, P=0.08) or PMBL (47%, P=0.001) patients. Median year of transplant was 2006 in both GCB and non-GCB and 2004 in PMBL.Results: Median (range) follow-up months in surviving GCB, non-GCB and PML patients were 63 (5-157), 29 (7-117) and 52 (10-133) months respectively. The 3-year cumulative OS were 52% (reference), 18% (P=0.09) and 46% (P=0.6). The 3-year cumulative PFS were 39%, 12% (P=0.1) and 41% (P=0.9) (Figure). When we restricted the comparison to patients who had chemosensitive disease and received RIC, the 3-year OS rates for GCB, non-GCB and PMBL were 47%, 25% (HR=0.6, P=0.3) and 44% (HR=0.9, P=0.9), respectively. The 3-year PFS rates were 37%, 10% (HR=0.6, P=0.2) and 44% (HR=0.7, P=0.8). Non-relapse mortality at 3-years was 29% (reference), 47% (P=0.1), and 35% (P=0.6). The incidence of acute II-IV GVHD was 24%, 27% and 29%. The incidence of extensive chronic GVHD was 34%, 54% (P=0.07) and 41% (P=0.5). The major cause of death in all 3 subgroups was disease progression (38%, 38%, and 33%), followed by acute GVHD 14%, 13%, and 33%.Conclusions: Our results suggest a tendency for inferior survival after alloSCT in non-GCB when compared to GCB and PMBL subtypes of DLBCL. This occurred despite the younger age in the non-GCB versus GCB group. Innovative approaches are needed to improve outcomes in non-GCB patients after alloSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Characteristics of progressive multifocal leukoencephalopathy clarified through internet-assisted laboratory surveillance in Japan

BackgroundProgressive multifocal leukoencephalopathy (PML), a rare but fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. As PML develops in individuals with various underlying disorders sporadically and infrequently, a nationwide survey of PML is difficult. This study was conducted to elucidate the characteristics of PML in Japan through an internet-assisted laboratory surveillance program.MethodsA diagnostic support system for PML was established using a real-time PCR assay of JCV DNA in cerebrospinal fluid (CSF), and requests for testing were received from clinicians via specialized websites. Medical histories of patients were collected through standardized questionnaires, and a database of CSF JCV loads and clinical information was created and analyzed.ResultsFor 4 years from April 2007 to March 2011, CSF specimens from 419 patients were tested. Forty-eight individuals were found positive for JCV DNA in their CSF and were diagnosed with PML. PML primarily occurred not only in HIV-positive patients (33.3%) but also in patients with hematologic disorders after receiving stem cell transplantation, chemotherapy, and/or immunosuppressive treatment (39.6%). The frequencies of PML cases among the subjects in these two categories were 20.3% and 23.5%, respectively. Although no significant features were observed with respect to CSF JCV loads in PML patients with an HIV infection or hematologic disorder, males were predominant in both groups (100% and 89.5%, respectively). The proportion of PML cases with autoimmune disorders (6.3%) or solid-organ transplants (2.1%) was smaller than those with HIV infection or hematologic disorders, probably due to the limited availability of therapeutic monoclonal antibodies and transplantation from brain dead donors.ConclusionsThe results suggest that the internet-assisted laboratory surveillance program might be a useful strategy for collecting precise real-time information on PML on a national level. The current database provides important background information for the diagnosis and treatment of patients with risk factors for PML.

PML IRIS: A Difficult Diagnosis (P02.271)

Objective: Consider Progressive Multifocal Leucoencephalopathy- Immune Reconstitution Inflammatory Syndrome (PML-IRIS) with worsening neurological symptoms and improved Cluster of Differentiation 4 (CD4) count and viral load. Background PML is a severe demyelinating disease of Central Nervous System, caused by the JC Polyomavirus. IRIS describes paradoxical worsening of pre existing infectious processes following initiation of Highly Active Anti Retroviral Therapy (HAART) and improvement in immunologic function. Design/Methods: Case Report from a Tertiary Medical Centre. Results: 41 year old man with Human Immunodeficiency Virus (HIV, non compliant with medications) presented with Right hand weakness. CD4 count was 53, Viral load was high, MRI Brain showed lesion in Left precentral gyrus, bright on Diffusion Weighted Imaging and moderate intensity on Apparent Diffusion Coefficient. He was thought to have subacute infarct, started on Aspirin, anticholesterol agent and HAART. Patient returned 6 weeks later with Right arm plegia, CD4 count had improved to 60 and viral load was undetectable. MRI Brain showed increased signal Left frontoparietal region with mild enhancement, no mass effect. Lumbar Puncture (LP) had normal cells, chemistry, and a viral PCR panel including JCV was negative. Patient was continued on HAART and sent home. He returned 3 weeks later with Right sided hemiplegia and aphasia. MRI Brain showed worsening mass effect, cavitation in the lesion with patchy nodular enhancement. Repeat CSF was normal including cytology and viral PCR. Brain biopsy showed inflammatory reactive infiltrate with abundant lipid laden macrophages, perivascular lymphocytes and rare cells reactive with JCV. A third CSF sample also revealed JCV detected at lower limit of quantitation. The patient was continued on HAART and Intra Venous (IV) Steroids started. His symptoms progressively improved. Conclusions: Increase in CD4 count and improved viral load can mount IRIS response in PML patients and IV Steroid therapy should be instituted without delay. Disclosure: Dr. Kannaditharayil has nothing to disclose.

JC Virus Encephalopathy Is Associated with a Novel Agnoprotein-Deletion JCV Variant

JC virus encephalopathy (JCVE) is a newly described gray matter disease of the brain caused by productive infection of cortical pyramidal neurons. We characterized the full length sequence of JCV isolated from the brain of a JCVE patient, analyzed its distribution in various compartments by PCR, and determined viral gene expression in the brain by immunohistochemistry(IHC). We identified a novel JCV variant, JCVCPN1, with a unique 143 bp deletion in the Agno gene encoding a truncated 10 amino acid peptide, and harboring an archetype-like regulatory region. This variant lacked one of three nuclear protein binding regions in the Agno gene. It was predominant in the brain, where it coexisted with an Agno-intact wild-type strain. Double immunostaining with anti-Agno and anti- VP1 antibodies demonstrated that the truncated JCVCPN1 Agno peptide was present in the majority of cortical cells productively infected with JCV. We then screened 68 DNA samples from 8 brain, 30 CSF and 30 PBMC samples of PML patients, HIV+ and HIV- control subjects. Another JCVCPN strain with a different pattern of Agno-deletion was found in the CSF of an HIV+/PML patient, where it also coexisted with wild-type, Agno-intact JCV. These findings suggest that the novel tropism for cortical pyramidal neurons of JCVCPN1, may be associated with the Agno deletion. Productive and lytic infection of these cells, resulting in fulminant JCV encephalopathy and death may have been facilitated by the co-infection with a wild- type strain of JCV.

Characterization of Non-Conserved HLA-A*0201 Binding T cell Epitopes of JC Virus T Antigen

JC virus-specific CD8+ cytotoxic T lymphocytes are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy. However, very few JC virus T cell epitopes restricted to MHC class I have been defined. Of the two HLA-A*0201-restricted JCV epitopes, VP1p36 and VP1p100, studies have shown that they are conserved T cell epitopes of polyomaviruses. The cross-recognition associated to these epitopes has complicated the efforts of understanding the dynamics of immune response to JC virus. Based on the previously identified HLA-A*0201 binding T cell epitope of Simian virus 40 T antigen P281–289 (KCDDVLLLL) and BK virus T antigen P558–566 (SLQNSEFLL), T cell epitopes of JC Virus T antigen P282–290 (KCEDVFLLM) and P557–565 (SLSCSEYLL) were identified. In this report, we demonstrated that JC Virus P282–290 and P557–565 were able to stimulate T cell responses in healthy donors’ PBMCs and CD8+ cytotoxic T lymphocytes raised with both peptides could recognize and lyse their targets. Most importantly, there were no T cell cross-recognitions between JC Virus, BK Virus and SV40 virus. Therefore, JCV T-ag epitopes P282–290 and P557–565 could be better antigen epitopes compared to VP1p36 and VP1p100 to study the dynamics of cellular immune response to JCV in PML patients. In addition, as a HLA-A*0201 binding T cell epitope, both peptides could be a valuable component of immunotherapies aiming at increasing the cellular immune response against JCV for the treatment of progressive multifocal leukoencephalopathy.

Inflammatory progressive multifocal leukoencephalopathy in human immunodeficiency virus–negative patients

Inflammatory progressive multifocal leukoencephalopathy (iPML) with enhancing magnetic resonance imaging (MRI) lesions and leukocyte infiltration occurs in human immunodeficiency virus (HIV)-infected individuals after highly active antiretroviral therapy (HAART) treatment. MRI diagnostic criteria for PML suggest that iPML does not occur in HIV-negative individuals. We studied pathologically proved PML (12 by biopsy, 9 with MRI, 32 at autopsy). HIV-negative (2/5) and -positive (2/4) PML patients had enhancing MRI lesions, correlated with CD3(+) lymphocyte infiltration. Inflammatory infiltrates occurred in the majority of HIV-negative (7/8) and HIV-positive/HAART (17/20) cases (p > 0.2), but in only 2 of 16 HIV-positive/non-HAART cases (p < 0.001). iPML showed radiographic and pathological similarity in HIV-positive/HAART and HIV-negative patients. HIV-negative iPML necessitates further consideration of MRI criteria for PML.

Role of the environment in the transmission of JC virus.

JC virus is etiologically associated with a fatal demyelinating disease known as PML. JCV produces persistent infections in the kidney and is excreted in the urine of healthy individuals and in the urine of PML patients. The characteristics of the JCV excreted in the environment have been studied by analyzing sewage samples from divergent geographical areas. The intergenic region of JCV strains detected in the sewage of Barcelona (Spain), Umeå (Sweden), Nancy (France), Pretoria (South Africa), Patras (Greece), Cairo (Egypt), Washington, D.C. (USA), and diverse areas of Northern India has been sequenced, and the phylogenetic analysis showed their relationships with JCV strains previously described in urine or clinical samples in these geographic areas. The JCV regulatory region of the JCV DNA detected in sewage presented archetypal or archetypal-like regulatory regions with the exception of one of the twenty clones obtained from a sewage sample of the area of Washington, D.C. that presented a tandem repeated structure. Infectivity studies showed that archetypal JCV present in the urine of a pregnant woman productively infected SVG cells. Also JC viral particles showed considerable stability in sewage at 20 degrees C and in front of treatments with acidic pH and trypsin. The high prevalence of JCV in urine and in sewage and the stability of the viral particles observed suggests that contaminated water, food, and fomites could be the vehicles of JCV transmission through the oral route. Virions partially degraded or noninfectious could be a source of JCV DNA and may represent an additional mechanism of entry of viral genes into cells.

JC virus-specific cytotoxic T lymphocytes in individuals with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by a reactivation of the polyomavirus JC (JCV) within a setting of immunosuppression. The nature of the immune response that contains replication of this virus is unknown. We have explored JCV-specific cellular immune responses in patients with PML and control subjects. JCV antigen-stimulated peripheral blood mononuclear cells (PBMC) of four human immunodeficiency virus (HIV)-infected patients who were survivors of PML and one HIV-uninfected patient recently diagnosed with PML lysed autologous B-lymphoblastoid cell lines expressing either the JCV T regulatory protein or the VP1 major capsid protein. This lysis was mediated by CD8(+) T lymphocytes and was major histocompatibility complex class I restricted. These cells were therefore cytotoxic T lymphocytes (CTL). JCV-specific CTL could not be detected in PBMC of three HIV-infected PML patients who had progressive neurologic disease and an eventual fatal outcome. These data suggest that the JCV-specific cellular immune response may play a crucial role in the containment of PML. This finding may also prove useful as a favorable prognostic marker in the clinical management of these patients.

A study on the influence of papovavirus upon encephalitis caused by SSPE agent

To investigate a possible interaction between the SSPE agent and papovaviruses, histopathological and statistical evaluations were made of encephalitis induced in hamsters by intracerberal inoculation with isolates from SSPE and PML patients, and with BK virus, alone or in combination. With SSPE virus alone, hamster brains showed a reduction of susceptibility to encephalitis with increasing age. A modification of the pathology of SSPE encephalitis was observed after administration of the PML isolate or BK virus: encephalitis was either enhanced or inhibited depending on the time the papovaviruses were administered. A possible mechanism of interaction between SSPE and papovaviruses is briefly discussed.