JC Virus Research Articles

Progressive Multifocal Leukoencephalitis of the Immunocompromised Subject: A Case Report from Zinder National Hospital

Progressive multifocal leukoencephalitis (PML) is a rare opportunistic infection of HIV-infected individuals. It is a viral infection caused by the John Cunningham (JC) virus, which occurs during the AIDS stage. An elderly patient immunosuppressed by HIV for more than 5 years presented to the HNZ SMIT with headache, vomiting, visual disturbances, speech disorders and numbness of the limbs, all of which had been evolving in a febrile context for more than seven months. Neurological examination revealed left hemiparesis, frontal syndrome, temporal syndrome and homolateral hemianopia. Cerebral computed tomography revealed multiple lesions of leukoencephalitis. PCR revealed JC virus. The patient was put on corticosteroids, rehydration and nursing care. The course was marked by a progressive deterioration in the patient's neurological condition, culminating in death. We report the clinical, biological and CT features of this progressive multifocal leukoencephalitis.

Frequent detection of IFN-gamma -producing memory effector and effector T cells in patients with progressive multifocal leukoencephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) is a rare and deadly demyelinating disease caused by JC virus (JCV) replication in the central nervous system. PML occurs exclusively in patients with severe underlying immune deficiencies, including AIDS and hematological malignancies. PML has also emerged as a significant threat to patients on potent new immunosuppressive biologics, including natalizumab in multiple sclerosis. Here, we developed an IFN-γ release assay (IGRA) that mainly detects JCV-specific effector memory T cells and effectors T cells in the blood. This assay was frequently positive in patients with active PML (with a positive JCV PCR in CSF) of various underlying immunosuppression causes (84% sensitivity). Only 3% of healthy donors had a positive response (97% specificity). The frequency of positivity also increased in multiple sclerosis patients according to the time on natalizumab (up to 36% in patients treated for more than 48 months, who are considered at a higher risk of PML). The results show this assay's frequent or increased positivity in patients with PML or an increased risk of PML, respectively. The assay may help to stratify the risk of PML.

Breast cancer, viruses, and human leukocyte antigen (HLA)

Several viruses have been implicated in breast cancer, including human herpes virus 4 (HHV4), human herpes virus 5 (HHV5), human papilloma virus (HPV), human JC polyoma virus (JCV), human endogenous retrovirus group K (HERVK), bovine leukemia virus (BLV) and mouse mammary tumor virus (MMTV). Human leukocyte antigen (HLA) is involved in virus elimination and has been shown to influence breast cancer protection/susceptibility. Here we investigated the hypothesis that the contribution of a virus to development of breast cancer would depend on the presence of the virus, which, in turn, would be inversely related to the success of its elimination. For that purpose, we estimated in silico predicted binding affinities (PBA) of proteins of the 7 viruses above to 127 common HLA alleles (69 Class I [HLA-I] and 58 Class II HLA-II]) and investigated the association of these binding affinities to the breast cancer—HLA (BC-HLA) immunogenetic profile of the same alleles. Using hierarchical tree clustering, we found that, for HLA-I, viruses BLV, JCV and MMTV were grouped with the BC-HLA, whereas, for HLA-II, viruses BLV, HERVK, HPV, JCV, and MMTV were grouped with BC-HLA. Finally, for both HLA classes, the average PBAs of the viruses grouped with the BC-HLA profile were significantly lower than those of the other, non BC-HLA associated viruses. Assuming that low PBAs are likely associated with slower viral elimination, these findings support the hypothesis that a defective/slower elimination and, hence, longer persistence and inefficient/delayed production of antibodies against them underlies the observed association of the low-PBA group with breast cancer.

Prevalence of Campylobacter Species, Helicobacter pylori, Human Papillomavirus, and JC Polyomavirus in Patients with Colorectal Cancer in Iran

Background: Colorectal cancer (CRC) is a complex disease with diverse gene expression patterns, which can arise from common adenomas or serrated polyps. The role of intestinal microbiota in the development of CRC is still a subject of debate. Objectives: This study aimed to explore the prevalence of a selection of gastrointestinal microbiota in Iranian patients with CRC. Methods: A total of 86 biopsy specimens (17 samples from normal tissues and 69 samples from cancer tissues) were analyzed from normal controls and patients with CRC. The presence of Helicobacter pylori, Campylobacter species (including C. jejuni, C. coli, C. upsaliensis, C. bovis, and C. fetus), as well as human papillomavirus (HPV) and JC polyomavirus (JCV) in tissue specimens, was examined using PCR. Results: The prevalence of the targeted bacterial and viral agents in CRC patients exhibited significant variations compared to normal controls. Notably, there was a higher prevalence of the Helicobacter genus in patients with CRC compared to normal controls. Patients with CRC were found to be at an increased risk of Campylobacter infection, with various Campylobacter species identified. Additionally, HPV and JCV genomes were detected in cancer samples at a higher rate than in normal controls. Conclusions: Our findings demonstrated a higher prevalence of the Helicobacter genus, Campylobacter species, HPV, and JCV in patients with CRC compared to normal controls. However, further research is required to elucidate the potential role of these bacterial and viral agents in the development of CRC.

Investigate the Relationship Between the Presence of JCV DNA and the Immunohistochemical Expression of CK2 0, CK7, and CDX2 in Colorectal Cancer

Abstract Background: Globally, colorectal cancer (CRC) is the most common malignancy and has a high fatality rate. Early childhood the John Cunningham virus or JC virus (JCV) infection persists throughout life and has been linked through multiple routes to colorectal cancer. The expression of cytokeratins 7 (CK7), 20 (CK20), and CDX2 have been investigated in a variety of primary and metastatic carcinomas, and their patterns of expression may be used to determine the site of origin of metastatic carcinomas. Objectives: The aim is to assess the relationship between JCV DNA and tumor markers (CK7, CK20, and CDX2) in patients with colorectal cancer, this study was carried out. Materials and Methods: Ninety CRCs (45 of which were squamous cell carcinomas and 45 of which were adenocarcinomas) had their paraffin sections randomly chosen, extracted, and immunostained for CK7, CK20, CDX2, and for the detection of JCV DNA by real-time (PCR). Results: JCV DNA was detected in 22 (24.4%) of AD-CRC and 24 (26.7%) of SCC-CRC (P = 0.004). The presence of JCV was significantly correlated with tumor stages (P = 0.04) and age categories (P = 0.05). Moreover, JCV presence was significantly correlated with all studied tumor markers (P < 0.05). Conclusion: JCV might play a role in the development of colorectal cancer, and CDX2, which is highly specific and sensitive as markers of colorectal origin should be helpful in the detection of intestinal adenocarcinomas.

Safety and effectiveness of disease-modifying therapies after switching from natalizumab

Introduction: One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined. Objective: The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity. Methods: This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity. Results: Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression (p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod (p < 0.001). Conclusion: Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity.

Insights into the genetic characteristics, clustering patterns, and phylogeographic dynamics of the JC polyomavirus, 1993 to 2023

The human JC polyomavirus (JCV) is a widespread, neurotropic, opportunistic pathogen responsible for progressive multifocal leukoencephalopathy (PML) as well as other diseases in immunosuppressed individuals, including granule cell neuronopathy, JCV-associated nephropathy, encephalitis, and meningitis in rare cases. JCV classification is still unclear, where the ICTV (International Committee on Taxonomy of Viruses) has grouped all the strains into human polyomavirus 2, with no classification on clade and subclade levels. Therefore, JCV strains were previously classified using different genomic regions, e.g., full-length, VP1, and the V-T intergenic region etc., and the strains were grouped into several types related to various geographic locations and human ethnicities. However, neither of these classifications and nomenclature contemplates all the groups described so far. Herein, we evaluated all the available full-length coding genomes, VP1, and large T antigen nucleotide sequences of JCV reported during 1993–2023 and classified them into four major phylogenetic clades, i.e., GI-GIV, where GI is further grouped into two types GI.1 and GI.2 with five sub-clades each (GI.1/GI.2 a-e), GII into three (GII a-c), GIII as a separate clade, and GIV into seven sub-clades (GIV a-g). Similarly, the phylogeographic network analysis indicated four major clusters corresponding to GI-GIV clades, each with multiple subclusters and mutational sub-branches corresponding to the subclades. GI and GIV clusters are connected via GI.1-e reported from Europe and America, GII, GIII and GIV clusters are connected by GII-b and GII-c strains reported from Africa, while GIV cluster strains are connected to the Russia-Italy JCV haplotype. Furthermore, we identified JCV-variant-GS/B-Germany-1997 (GenBank ID: AF004350.1) as an inter-genotype recombinant having major and minor parents in the GI.1-e and GII-a clades, respectively. Additionally, the amino acid variability analysis revealed high entropy across all proteins. The large T antigen exhibited the highest variability, while the small t antigen showed the lowest variability. Our phylogenetic and phylogeographic analyses provide a new approach to genotyping and sub-genotyping and present a comprehensive classification system of JCV strains based on their genetic characteristics and geographic distribution, while the genetic recombination and amino acid variability can help identify pathogenicity and develop effective preventive and control measures against JCV infections.

A case of a cerebellar form of progressive multifocal leukoencephalopathy in a patient undergoing peritoneal dialysis.

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system, is caused by the reactivation of the polyomavirus JC virus (JCV). It favors the cerebrum and typically occurs in patients with immunodeficiencies, with a progressive course and fatal outcome in the majority of cases. However, the cerebellar form of PML, characterized by isolated posterior fossa lesions, such as those in the cerebellum or brainstem at disease onset, is rare, and reports of its occurrence in peritoneal dialysis (PD) patients are lacking. In this paper, we describe a rare case of a cerebellar form of PML in a PD patient. A 64-year-old man undergoing PD was referred to our hospital for anorexia, nausea, and vomiting in the past month. He had finger-to-nose test abnormalities, gaze-directed nystagmus, and scanning speech. He was diagnosed with the cerebellar form of PML based on his progressive cerebellar symptoms, the typical magnetic resonance imaging findings, and the presence of JCV-DNA in the cerebrospinal fluid polymerase chain reaction test. He developed nocturnal delirium, aggravated disquiet, and died of pneumonia on the 69th day. Clinicians should consider the cerebellar form of PML as a differential diagnosis if PD patients develop progressive cerebellar symptoms.

Molecular epidemiology and risk factors associated with BK and JC polyomavirus urinary shedding after kidney allograft.

Polyomaviruses BK (BKPyV) and JC (JCPyV), belonging to the Polyomaviridae, are responsible for human pathologies. In kidney transplant recipients, BKPyV replication can lead to irreversible nephron damage whereas JCPyV replication remains asymptomatic. Concomitant replication is rare and potential competition between the infections has been described. The aim of this retrospective case-control study was to describe the molecular epidemiology and risk factors associated with BKPyV and JCPyV replication in a cohort of kidney transplant recipients. In total, 655 urine samples from 460 patients were tested for BKPyV and JCPyV DNA. Positive samples were submitted to strain genotyping. Demographic and clinical characteristics were also compared. Isolated JCPyV and BKPyV was found in 16.5% and 23.3% of patients, respectively; co-replication was rare (3.9%). BKPyV strains Ib-2, Ib-1, and IVc-2 were the most prevalent. JCPyV strains mostly belonged to genotypes 4 and 1B. During follow-up, JCPyV shedding significantly reduced the risk of BKPyV DNAuria, with an odds ratio of 0.57 (95% confidence interval: 0.35-0.99), and was associated with better prognosis than BKPyV replication, based on the estimated glomerular filtration rate. Molecular epidemiology of BKPyV and JCPyV strains in our region was similar to previous studies. This study suggests that JCPyV is benign and appears to limit damaging BKPyV replication. JCPyV DNAuria screening could thus be a useful strategy to predict BKPyV-related outcomes.

Focal haemorrhage as atypical feature on MRI in progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a severe progressive demyelinating disorder caused by the suppression of cell-mediated immunity and is diagnosed by typical imaging features on MRI and confirmed by the identification of the JC virus on CSF. We present a case of HIV positive adult male who presented with progressive hemiparesis and spastic dysarthria over 3 months duration, and MRI showed white matter T2 hyper, T1 isointense and peripherally diffusion restricting lesion in the right frontoparietal region with an additional focal haemorrhage within the lesion, which misled us away from considering PML. However, repeat imaging showed progression of the lesion and CSF analysis showed John Cunningham (JC) virus, confirming the diagnosis.

Effect of Cigarette Smoking on Clinical and Molecular Endpoints in COPD Patients.

Cigarette smoking is a primary contributor to mortality risks and is associated with various diseases. Among these, COPD represents a significant contributor to global mortality and disability. The objective of this study is to investigate the effect of smoking on a selected battery of variables, with an emphasis on DNA damage. A total of 87 elderly patients diagnosed with COPD, divided into three groups based on their smoking history (current, former, never-smokers), were evaluated using a cross-sectional approach. Clinical features including mortality and inflammatory/oxidative parameters (Lymphocytes/Monocytes, Neutrophils/Lymphocytes, Platelets/Lymphocytes ratio), SII, MDA, 8-Oxo-dG, and IL6 (ELISA assay), as well as DNA damage (comet assay), were investigated. Virus infection, i.e., influenza A virus subtype H1N1, JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), and Torquetenovirus (TTV), was also tested. Current smokers exhibit higher levels of comorbidity (CIRS; p < 0.001), Platelets/Lymphocytes ratio (p < 0.001), systemic immune inflammation (p < 0.05), and DNA damage (p < 0.001). Former smokers also showed higher values for parameters associated with oxidative damage and showed a much lower probability of surviving over 5 years compared to never- and current smokers (p < 0.0017). This study showed a clear interaction between events which are relevant to the oxidative pathway and cigarette smoking. A category of particular interest is represented by former smokers, especially for lower survival, possibly due to the presence of more health problems. Our findings raise also the attention to other parameters which are significantly affected by smoking and are useful to monitor COPD patients starting a program of pulmonary rehabilitation (DNA damage, inflammation parameters, and selected viral infections).

#1038 Progressive multifocal leukoencephalopathy in kidney transplant recipients: a retrospective multicenter nationwide cohort study

Abstract Background and Aims Progressive multifocal leukoencephalopathy (PML) is a serious opportunistic infectious disease affecting the central nervous system caused by JC virus. While extensively studied in patients with HIV infection, haematological malignancies, or undergoing immunotherapies, there is a lack of data concerning kidney transplant recipients (KTRs). Method We performed a retrospective, multicentric, nationwide study. We contacted all kidney transplantation centres in France to gather all cases of PML. We obtained the count of patients with a functional kidney allograft using the registry of the French regulatory agency. Results We collected 24 cases of PML. Between 2012 and 2021, the estimated minimal nationwide incidence of PML was 4.7/100 000 patient-years. The median duration from kidney transplantation to PML was 88 months (interquartile range: 9 to 355). Eight patients (33%) had been exposed to belatacept (median exposure: 18.5 months). Almost all patients underwent reduction or withdrawal of immunosuppressive drug doses and 13 (54%) received a specific treatment. Fifteen patients (65%) died within one year after diagnosis. Conclusion In this nationwide study, PML incidence rate in KTRs was at least 4.7/100 000 patient-years resulting in an alarming 65% mortality rate within a year despite immunosuppressants doses decrease or withdrawal. Further investigations are warranted to demonstrate the efficacy of specific treatments and confirm a potential association between belatacept exposure and PML occurrence, as suggested by our study.

#2256 Safety and effectiveness of avacopan beyond 52 weeks: experience to date in the Early Access Program (EAP)

Abstract Background and Aims ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), is characterized by a high burden of organ damage, as well as increased mortality [1]. Both the disease itself and the immunosuppression required for its management contribute significantly to poor prognosis [2]. Avacopan is a first-in-class C5aR1 antagonist that demonstrated efficacy and safety over 52 weeks in patients with GPA or MPA, and was associated with a significantly lower requirement of glucocorticoids for disease management [3]. Significant data on long-term avacopan use in the context of real-life settings are sparse. Here, we describe experience with avacopan in 59 patients with GPA or MPA treated beyond 52 weeks within an ongoing Early Access Program (EAP). Method Patients with newly diagnosed or relapsing severe, active GPA or MPA were treated in the EAP. Safety data, including lack of effect and other events (i.e., relapse or worsening of disease) in these patients were recorded in a CSL Vifor safety database from Feb 2019 – Dec 2023. We performed analysis of these data for patients treated beyond 52 weeks. Results 237 patients received ≥ 1 dose of avacopan with a median overall treatment duration of 7 months (range 1-45) at the time of this analysis. 43 of 237 patients had at least one adverse event (AE) reported (18.1%) with a median of 2 (range 1-11) AEs per patient; 19/237 (8.0%) patients experienced a serious AE (SAE). Most of the reported AEs belonged to the System Organ Classes (SOC) of infections and infestations, and gastrointestinal disorders, with COVID-19 being the most frequently-reported event. At the time of this analysis, 59 patients continued treatment beyond 52 weeks, with a median overall duration of treatment of 16 months (range 13-45). Within this group, 12 of 59 patients experienced at least one AE (20.3%) with a total of 46 AEs. 9/ 12 patients reported AEs during the first 52 weeks treatment, while in 3 patients the date of AE occurrence was not available (Table 1). The results in these 59 patients are summarized below. 6 patients experienced at least one SAE (7 SAEs in total). As in the overall EAP population, most of the reported AEs belonged to the SOC of gastrointestinal disorders, followed by infections and infestations, with COVID-19 being the most common AE occurring in 3 patients. 18 AEs were assessed as related to avacopan, with 3 events in 2 patients being classified as serious (deep vein thrombosis [DVT] in one patient, lower urinary tract symptoms and JC polyomavirus test positive in the second). The patient experiencing DVT temporary discontinued avacopan. In the patient who developed lower urinary tract symptoms with active replication of JC virus (1.728.405 copies/mL), avacopan was permanently withdrawn. According to the reporter, the concomitant use of prednisone, rituximab and denosumab could have contributed to these events. Three patients experienced events implying worsening of underlying disease. These events occurred within the first 52 weeks of treatment. The first patient experienced a vasculitis flare 6 months following avacopan initiation that coincided with an unintended dose reduction to 20 mg BID due to a product supply issue. The second patient experienced a worsening of known GPA related mononeuritis multiplex, possibly induced by concomitant treatment with isoniazid and a likely result of pharmacological interaction between rifampicin and avacopan. The third patient experienced an increase of creatinine, proteinuria and microhematuria in the context of avacopan withdrawal due to other events. Conclusion These results confirm that avacopan has a manageable safety profile with the potential to be effective beyond 52 weeks in sustaining disease control. Limitations of this analysis include potential underreporting, incomplete data and no control group.

John Cunningham Virus and Progressive Multifocal Leukoencephalopathy: A Falsely Played Diagnosis.

Progressive Multifocal Leukoencephalopathy (PML) is a possibly fatal demyelinating disease and John Cunningham Polyomavirus (JCPyV) is believed to cause this condition. The so-called JCPyV was initially reported in lymphoma and Human Immunodeficiency Virus (HIV) cases, whereas nowadays, its incidence is increasing in Multiple Sclerosis (MS) cases treated with natalizumab (Tysabri). However, there are conflicting literature data on its pathology and diagnosis, whereas some misdiagnosed reports exist, giving rise to further questions towards the topic. In reality, the so-called PML and the supposed JCPyV are not what they seem to be. In addition, novel and more frequent PML-like conditions may be reported, especially after the Coronavirus Disease 2019 (COVID-19) pandemic.

Absence of JC polyomavirus in stool samples of patients with multiple sclerosis despite high anti-JCV antibodies in serum

BackgroundNatalizumab is an effective treatment for relapsing multiple sclerosis (MS). During therapy, individuals are at increased risk of developing progressive multifocal leukoencephalopathy (PML). So far, the relevant reservoir for PML-type JC polyomavirus (JCV) remains elusive. We here tested if the detection of JCV-DNA in stool of persons with MS treated with natalizumab could be a future tool for PML risk assessment. MethodsThe presence of JCV-DNA in stool, urine, and whole blood of MS patients treated with natalizumab and known serum anti-JCV antibodies index values (IV) was studied. Different DNA extraction methods, real-time (RT) and droplet digital (dd) PCR techniques were compared. JCV isolates were screened for PML-associated variants by sequencing. ResultsThirty MS patients treated with natalizumab were screened. For 21 patients, blood, stool, and urine samples were available. These patients were stratified according to their serum anti-JCV antibody IV (high (>1.5, n = 12); medium (1.5–0.9, n = 2); low (<0.9, n = 1); negative (n = 6)). JCV-DNA could not be detected in the whole blood or stool samples. Four urine samples had measurable JCV-DNA, ranging from 1.71×104–1.07×108 international units (IU)/mL detected by RT-PCR, corresponding to 4.62×104–9.85×106 copies/mL measured by ddPCR. All JCV variants were wild-type and derived from patients with high antibody IV. ConclusionStool-specific DNA extraction methods provided the highest quality of DNA, while the sensitivity of ddPCR and RT- PCR was comparable. Our findings do not support assessing stool samples for PML risk stratification in persons with MS. Further studies are needed to explore where PML-associated viral variants arise.

PD-1 mediates brain resident memory T cell formation and virus control

Abstract Programmed cell death protein 1 (PD-1) is upregulated in T cells of patients with progressive multifocal leukoencephalopathy (PML), a demyelinating disease caused by infection of the central nervous system (CNS) by JC polyomavirus (JCPyV). Studies have exhibited variable success in treating PML with PD-1 blockade, denoting a need to understand the function of PD-1 in polyomavirus CNS infection. PD-1 is highly expressed on functional CD8 T cells in the brain after intracerebral inoculation of mouse polyomavirus (MuPyV), which we use to model JCPyV CNS infection. We hypothesized that PD-1 signaling on CD8 T cells regulates the differentiation of virus-specific brain resident-memory T cells (bTrm). Using an inducible global PD-1 knockout mouse model, we show that deleting PD-1 during acute MuPyV infection results in the transition of virus-specific CD8 T cells toward a more resident-memory-like phenotype. PD-1 deletion during persistent infection results in higher T cell counts as well as reduced viral loads. To clarify the effects of CD8 T cell-specific PD-1 signaling, we adoptively transferred inducible PD-1 knockout CD8 T cells into recipient mice. In contrast to global deletion, CD8 T cell-specific loss of PD-1 led to a lower frequency in resident-memory-like cells. These data suggest that acute global PD-1 loss promotes bTrm formation, which may be independent of PD-1 signaling on CD8 T cells, and that PD-1 loss during persistent infection may promote better viral control.

P028 Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus

Abstract Background/Aims Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that develops following the reactivation of the John Cunningham virus (JCV) that in rare circumstances can occur in autoimmune disorders such as systemic lupus erythematosus (SLE). We present a 75-year-old female with SLE who had been treated with immunosuppressive therapy (mycophenylate and steroids) for one year. Methods A 75 year-old female presented with sub-acute deterioration of physical and cognitive function over the course of a few months including memory loss, ataxia, dysgraphia, word finding difficulty, confusion, low mood and reduced oral intake. Neurological examination revealed receptive and expressive aphasia, gaze fixation, unilateral weakness, brisk reflexes with positive plantar reflex and rigidity. A diagnosis of PML was made due to the detection of JC virus in the cerebrospinal fluid (234 copies/ml) and brain MRI findings consistent with the disease. Haematology results showed a profound lymphopenia (0.1x109 ). Mycophenolate was held and she was commenced on increasing doses of Mirtazapine up to 45mg. Clinical review at four months found marked improvement in her cognitive and physical abilities. Repeat CSF analysis found JC virus to be undetectable. Results PML has a 20-fold greater incidence in SLE when compared with the general population. Lymphopenia is a common finding in patients with SLE and has been found to correlate with both the risk and severity of opportunistic infections. The cause of this can be multifactorial and immunosuppressive drugs are often implicated however SLE in isolation can cause severe CD4+ lymphopenia leading to an increased risk of PML reactivation. This case demonstrates the importance of monitoring lymphocyte counts in SLE. Current guidance suggests adjusting regimes of immunosuppressive therapy if lymphocyte counts fall below 1x109 however further guidance on its management may be warranted. The heterogenous manifestation of SLE can make differentiating between the neurological syndromes associated with rheumatic disease and PML challenging. Given the management of PML is vastly different to that of SLE in regards to introduction or withdrawal of immunosuppressive therapies, there should be a high index of clinical suspicion in the early stages of investigation. In vitro studies have explored the possibility of mirtazapine (a 5-HT2A antagonist) providing a low-risk treatment option for those with SLE and this warrants further research into its efficacy in treating or preventing PML in this cohort. Our patient had improved symptomology after cessation of mycophenolate and the commencement of Mirtazapine. Conclusion PML is a rare complication of SLE but should be considered in patients admitted with neuropsychiatric presentations, the use of Mirtazapine may provide a low-risk treatment strategy. Disclosure D. Babla: None. Y. Suleman: None. A. Whittington: None. S. Hamdulay: None.

Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab

Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay. To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment. This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023. Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year). Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed. Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment. The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

JC Virus in Kidney Transplant Population: Are We Cautious Enough?

The John Cunningham virus (JCV) is a polyomavirus that usually infects people at a young age and does not cause any symptoms in immunocompetent individuals. However, in immunocompromised individuals, such as kidney transplant recipients, JCV can cause severe and potentially fatal disease. Unfortunately, JCV has not been researched as extensively as the BK virus and is not mentioned in relevant kidney transplant guidelines. This lack of attention to JCV can lead to less consideration in kidney transplant patients' care. Surveillance using locally available diagnostic methods is of the utmost importance. The presence of JCV can be diagnosed with urine decoy cells, viruria, or viremia verified by the PCR method. A low threshold for considering JCV as a possible cause of any neurological or renal dysfunction in kidney transplant recipients must be maintained. In such cases, kidney and brain biopsy are indicated. Maintaining the appropriate immunosuppression while avoiding over-immunosuppression to prevent JCV disease is crucial, and the approach should be individual, according to overall immunological risk. We hypothesize that the presence of the JCV can indicate overt immunosuppression and identify kidney transplant recipients more prone to opportunistic infections and diseases, including some malignancies. To explore that, future observational studies are needed.

Final outcomes from a phase 2 trial of posoleucel in allogeneic hematopoietic cell transplant recipients

AbstractAllogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) after infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T-cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled allo-HCT recipients at high risk based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes of <180/mm3; or use of T-cell depletion. Posoleucel dosing was initiated within 15 to 49 days of allo-HCT and subsequently every 14 days for up to 7 doses. The primary end point was the number of CSIs due to the 6 target viruses by week 14. Of the 26 patients enrolled, only 3 (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ enzyme-linked immunosorbent spot assay was associated with viral control. Persistence of posoleucel-derived T-cell clones for up to 14 weeks after the last infusion was confirmed by T-cell–receptor deep sequencing. Five patients (19%) had acute graft-versus-host disease grade 2 to 4. No patient experienced cytokine release syndrome. All 6 deaths were due to relapse or disease progression. allo-HCT recipients at high risk who received posoleucel had low rates of CSIs from 6 targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution. This trial was registered at www.ClinicalTrials.gov as #NCT04693637.