JC Polyomavirus Infection: A Narrative Review

Abstract

Progressive multifocal leukoencephalopathy (PML) is a devastating and often fatal central nervous system infection caused by John Cunningham polyomavirus virus (JCPyV). PML results from JCPyV reactivation in the setting of impaired cellular immunity in patients with HIV, organ transplantation, severe inflammatory disease, and an increasing number of modern treatments for cancer and autoimmune diseases. The presence of clinical and imaging manifestations consistent with the diagnosis coupled with the demonstration of JCPyV by PCR in cerebrospinal fluid (CSF) are considered diagnostic. Since there are no effective antiviral treatments available, restoring immune function is a key component in PML treatment. Novel immunotherapeutic approaches can ameliorate PML. Immunotherapeutic interventions, such as use of checkpoint inhibitors and viral specific T-cell, have shown promising results, but additional data are needed. In this review, we summarize the available data on risk factors for JCPyV neurological syndrome, clinical, laboratory, and radiological features, and propose an algorithm for management.

Key Summary Points

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal disease of the central nervous system caused by John Cunningham polyoma virus (JCPyV).

Impairment of cellular immunity such as in patients with human immunodeficiency virus (HIV) or patients on immunosuppressive drugs can lead to reactivation of JCPyV.

Reversal of the underlying immunosuppression is key in the treatment of PML.

Novel immunotherapeutic approaches, including checkpoint inhibitors and the use of viral specific T-cell, can ameliorate PML.

Introduction and Background

John Cunningham polyoma virus (JCPyV) is a human polyomavirus of the Polyomaviridae family, which also includes BK virus and simian vacuolating virus 40. JCPyV infection typically occurs in childhood via horizontal transmission through long-term cohabitation, most commonly from parent to child [1]. Oral, respiratory, and fecal–oral routes of transmission have been suggested [2]. Seroconversion increases with age and reaches up to 80% by the age of 70 years [3–6]. JCPyV commonly establishes lifelong latency in the kidney, bone marrow, and lymphoid organs in the general population. However, in patients with prolonged and profound defects in cell-mediated immunity, JCPyV can reactivate from sites of latency and become a pathogenic virus, infecting glial cells and causing progressive multifocal leukoencephalopathy (PML) [7].

In this review, we aim to provide a comprehensive overview of JCPyV-associated neurological syndrome, main risk factors in the era of immunomodulators and biological treatments, laboratory and radiological features, and an approach to treatment based on current knowledge. We searched online databases, including PubMed and Google scholar, for articles related to JCPyV and progressive multifocal leukoencephalopathy from inception to October 2024. We included studies with clinical data regarding JCPyV-associated neurological disease and its treatments, including randomized controlled trials, observational studies, case series, and case reports. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Clinical Manifestations

Classic Progressive Multifocal Leukoencephalopathy (PML)

PML results from infection of mainly oligodendrocyte cells and astrocytes; however neuronal cells are also infected. The resulting pathology is demyelination of brain tissue, and the neurological deficits are in accordance with areas of demyelination. These deficits usually present subacutely, and can include motor, sensory, or cognitive deficits, hemianopsia, aphasia, gait disturbances, and others. The disease usually spares the optic nerves and the spinal cord [8]. When demyelinating lesions involve the cortex, patients may present with seizures which, however, are reported in less than 20% of PML patients [9].

PML–Immune Reconstitution Inflammatory Syndrome (PML-IRIS)

PML-IRIS cases are characterized by new onset or clinical worsening of PML due to the inflammatory process secondary to the immune reconstitution. These lesions associated with PML-IRIS are contrast-enhanced on magnetic resonance imaging (MRI). PML-IRIS occurs generally in HIV patients with rising CD4 T-cell count after receiving antiretroviral therapy (ART) [10]. In patients with drug-associated PML, drug withdrawal and immune reconstitution can predispose IRIS [11–13]. The most studied example is in patients with natalizumab-associated PML (NZ-PML), who may also present with PML-IRIS after drug cessation or plasma exchange [13]. These patients will develop PML IRIS 3–6 weeks after treatment cessation or plasma exchange [14], and it might be more severe than PML-IRIS in HIV patients since the immune system is intact in multiple sclerosis (MS) patients. Rarely, solid organ transplant (SOT) recipients (i.e., liver or kidney transplant recipients) may develop PML-IRIS following the reduction of immunosuppression [15].

Corticosteroids are used for the treatment of PML-IRIS according to data from several studies which reported a beneficial effect [10, 14, 16, 17]; however, a randomized controlled trial (RCT) of corticosteroids for treatment of PML-IRIS is lacking. Therefore, implementing corticosteroids in the treatment of PML-IRIS should be considered when there are typical enhanced brain lesions, edema or mass effect, and evidence of clinical deterioration.

JCPyV Granule Cell Neuronopathy (JCPyV GCN)

JCPyV granule cell neuronopathy (JCPyV GCN) is caused by infection of granule cell neurons in the cerebellum. This rare syndrome was described as a distinct syndrome of cerebellar atrophy without typical radiological manifestations of PML, but can also be seen in classical PML patients as a combination of cerebellar atrophy with infratentorial or supratentorial demyelinating lesions [18–20]. This rare syndrome was described in acquired immunodeficiency syndrome (AIDS) patients [21, 22], and in non-HIV-infected patients [23, 24], including a patient with sarcoidosis [25] and patients treated with natalizumab [26] and ruxolitinib [27].

JCPyV Encephalopathy (JCVE)

JCVE is extremely rare condition characterized with gray matter disease caused by productive infection of cortical pyramidal neurons, without white matter involvement [8]. This unique syndrome was described in HIV-infected patients [28] and in non-HIV patients, including lung cancer [29], myelofibrosis [30], and ruxolitinib treatment [31], all proven by autopsies or histological examination.

JCPyV Meningitis

There are several case reports of patients with meningitis and JCPyV detection in cerebrospinal fluid (CSF), including patients with rheumatological diseases [32] and roxulitinib treatment [33]. However, it is not clear whether infection is due to JCPyV primary infection or reactivation.

Underlying Conditions and Risk Factors for PML

PML was initially described in patients with hematological malignancies [34–37], which is the most common or second most common underlying condition after AIDS (CD4 counts < 200 cell/ml) [38]. However, since the wide spread use of ART, PML prevalence among HIV-infected patients has declined [39, 40], although it occasionally occurs in AIDS patients with much higher CD4 cell counts [40, 41]. Auto-immune disorders are considered as the underlying condition in approximately a quarter of PML patients [38, 42, 43], including MS, systemic lupus erythematosus, rheumatoid arthritis, and less commonly in systemic sarcoidosis, dermatomyositis, Behçet disease, polymyalgia rheumatica, Goodpasture syndrome, and cryoglobulinemic vasculitis [43], most but not all treated with immunomodulatory drugs [44–46]. PML is also a potential complication in patients receiving hematopoietic stem cell transplant (HSCT) or following SOT, treated with immunosuppressive therapy to prevent graft rejection [47–51]. Primary immunodeficiency (PID) is a rare cause of PML [52, 53], with several case reports described in various diseases, mostly with combined B and T-cell impairment.

Immunosuppressive and immunomodulatory drugs are currently a major risk factor for PML (see Table 1 for list of potentially causative drugs). JCPyV reactivation is the leading safety concern with natalizumab, a monoclonal anti-α4 integrin antibody, which inhibits the adhesion of leukocytes to endothelial cells, including in the central nervous system, and is used in the treatment of relapsing–remitting MS [54]. Patients with MS who are JCPyV seropositive, receiving prolonged natalizumab therapy and had previous immunosuppression, are at the highest risk for developing PML during natalizumab therapy [55]. Therefore, natalizumab is contra-indicated in patients who have had PML and should not be used in patients with impaired cell-mediated immunity, such as concurrent hematologic or rheumatologic disease [8, 56].

Table 1.

Drug-associated progressive multifocal encephalopathy (PML)^a

Drug	Mechanism of action		Risk for PML based on available evidenceb	FDA boxed warningc
Adalimumab	Anti-TNFα	[128, 129]	Low, case report
Azathioprine	Anti-metabolite, purine analogues	[38, 130]	Low, case report
Belatacept	T-cell co-stimulation blocker	[132]	Low, case report
Bendamustine	Alkylating agent	[133]	Low, case report
Bortezomib	Proteasome inhibitor	[131, 134]	Low, case report
Brentuximab vedotin	Anti-CD30	[131, 135, 136]	Intermediate, case series	V
Cyclophosphamide	Alkylating agent	[137]	Intermediate, case series
Daratumumab	Anti-CD38	[134, 138]	Intermediate, case series
Dimethyl fumarate	Activation of Nrf2 pathway	[130, 139, 140]	Intermediate, case series
Eculizumab	Anti-complement protein C5	[141]	Low, case report
Efalizumab	Anti-CD11a	[142, 143, 144]	High risk, withdrawal from market due to PML risk
Elotuzumab	Activation of NK cell	[145]	Low, case report
Fingolimod	Sphingosine-1-phosphate receptor modulator	[106, 130, 131, 146, 147]	Intermediate, case series
Fludarabine	Purine analogue	[131, 148, 149]	Intermediate, case series
Ibrutinib	Bruton's tyrosine kinase inhibitor	[36, 36, 150, 151]	Intermediate, several case reports
Idelalisib	PI3K Delta inhibitor	[152, 153]	Intermediate, case series
Infliximab	Anti-TNFα	[154]	Low, case report
Leflunomide	Immunomodulatory	[155, 156]	Intermediate, several case reports
Lenalidomide	Immunomodulatory	[131, 157, 158]	Intermediate, several case reports
Methotrexate	Anti-folate	[159, 160]	Low, case report
Mycophenolate mofetil	Anti-metabolite	[86, 161–164]	Intermediate, several case report
Natalizumab	Anti-alpha4-integrins	[115, 165, 166]	High risk	V
Obinutuzumab	Anti-CD20	[167–169]	Intermediate, several case reports	V
Ocrelizumab	Anti-CD20	[165, 170, 171]	Intermediate, several case reports
Ofatumumab	Anti-CD20	[172]	Low, case report
Polatuzumab vedotin	CD79b-directed antibody–drug conjugate	[173]	Low, case report
Pomalidomide	T-cell-mediated cytotoxicity	[131, 174–176]	Intermediate, several case reports
Rituximab	Anti-CD20	[130, 144, 162, 177–179]	Intermediate, case series	V
Ruxolitinib	JAK inhibitor	[27, 31, 33]	Intermediate, several case reports
Tacrolimus	Calcineurin inhibitor	[84, 180]	Low, case report	v
Teclistamab	Bispecific T-cell engager (BITE)	[181]	Low, case report
Temozolomide	Alkylating agent	[182]	Intermediate, case series
Thalidomide	Immunomodulatory	[183, 184]	Intermediate, several case reports
Tocilizumab	Anti-IL6	[160]	Low, case report

^aOther than natalizumab, the risk of PML with other drugs is less well established, and risk depends on patient characteristics including previous immunosuppression, therapy characteristics including duration of therapy and combination therapy, and baseline JCPyV serostatus. For natalizumab only, the risk of PML is well established and acknowledged. An algorithm to asses the risk in a specific patient is provided by the manufacturer (PML tools and Stratify JCV, at https://biogenlinc.co.uk/en/products/ms-portfolio/tysabri/pml/)

^bDrugs are classified to low, intermediate, and high risk for PML according to available data, mostly from case reports and case series

^cFDA black box signifies that there is credible evidence linking the drug to PML; however, the presence of such a warning does not necessarily indicate that the drug poses a higher risk of PML compared to others without the warning. It reflects the FDA's assessment of the available evidence and the need to inform healthcare providers and patients of the potential risk

Although every case of PML in otherwise healthy people should raise prompt investigation for immune deficiency (e.g., idiopathic CD4 lymphopenia), in a small minority of patients PML can occur without overt immune deficiency [57] or chronic liver [58] or kidney disease [59] as the only risk factor [61–64].

Diagnosis

No single criterion establishes the diagnosis of PML; rather, it requires clinical, imaging, and virological evidence. A consensus statement from the American Academy of Neurology Neuroinfectious Disease Section (2013) published diagnostic criteria for PML [60]. These guidelines address the more common scenarios in which histopathology is not available, and distinguish between definitive diagnosis (compatible clinical features, imaging findings, and positive PCR for JCPyV in CSF), probable (positive PCR with either clinical or imaging findings), possible (either positive PCR alone or negative PCR with both clinical and imaging findings), and no PML diagnosis (clinical or imaging findings compatible with PML as a single criterion).

Pathological Findings

Histopathological characteristics of PML in brain biopsy consists of multifocal demyelination, giant bizarre astrocytes with lobulated hyperchromatic nuclei, and loss of oligodendrocytes, with the remaining enlarged and contain intranuclear inclusions of viral particles [61]. The presence of the virus in the tissue can be confirmed by immunohistochemistry, in situ hybridization, and PCR [62–65]. Although the most accurate diagnosis of clinically suspected PML is made by needle brain biopsy and microscopic examination, this approach can sometimes fail to confirm the diagnosis of PML, due to small biopsy volume [66].

Radiological Findings

Brain imaging has an important role in PML diagnosis, where cranial MRI is the modality of choice in detecting white matter lesions of PML [67, 68]. The typical lesions are hyperintense on T2-weighted fluid-attenuated inversion recovery, and involve the subcortical and juxtacortical white matter, with a decreased signal on T1-weighted images [69]. The frontal lobes and parieto-occipital regions are the regions that appear to be most commonly affected, but basal ganglia, external capsules, and posterior fossa structures (cerebellum and brainstem) may also be seen [60]. Contrast enhancement is generally associated with an inflammatory stage, although it can also be observed focally during active PML [70]. In active expanding lesions, restricted diffusion can be seen at the edges of the lesions [71]. Another unique finding that has been described in some cases is a band-like paramagnetic shift which is visible on susceptibility-weighted imaging at the gray matter–white matter junction [72]. Recently, the MR imaging “shrimp sign” [73–75], a cerebellar white matter lesion, was identified in patients with cerebellar PML, with a sensitivity of 85% and a specificity of 100% [73].

Laboratory Studies

CSF analysis is essential for the diagnosis of PML and to exclude other diseases. There are no specific CSF abnormalities that is strongly associated with PML [76, 77], thus a quantitative PCR testing for JCPyV in the CSF is recommend where the sensitivity of the ultrasensitive PCR techniques is above 95% [60]. False negative CSF results can occur in the setting of immune reconstitution after starting ART therapy in patients with HIV when there is a decreased viral replication and clearance of the virus from the CSF [49]. False positive CSF results are rarely encountered when CSF is contaminated with blood in patients with JCPyV viremia without PML [78]]. Two nested case–control studies, evaluating JCPyV viremia retrospectively in HIV patients who developed PML versus HIV individuals without PML diagnosis, did not find any difference in the frequency of prior viremia to PML diagnosis in the two years prior to PML diagnosis [79]].

In cases where CSF is not available or JCPyV not detected in CSF via PCR, PCR testing of JCPyV in plasma might complement PML diagnosis. In a retrospective study that analyzed plasma samples from PML patients and from controls without PML, JCPyV viremia was detected in 48% of PML patients and in 3% of the controls. In this study, the diagnostic sensitivity and specificity of plasma PCR for JCPyV were 48% and 97%, respectively [80].

Treatment

Immune Reconstitution

To date, there has been no specific treatment for PML, thus the main approach focuses on immune reconstitution. Based on our experience, combined with the limited published data, we propose a treatment algorithm to offer general guidance in the management of PML patients (Fig. 1). Given the rarity of the disease, the limited literature, and the absence of approved treatments, this algorithm should be interpreted with caution, and management should be tailored on a case-by-case basis. Generally, in patients with HIV, CD4+ cell count > 50 cells/µL at diagnosis of PML is significantly associated with reduced mortality [81], and immune reconstitution after initiation of ART has been shown to stop progression, improve neurological outcomes, and improve survival [82, 83]. In non-HIV-infected patients with PML, efforts should be made to restore T-cell function by reduction of immunosuppressive treatment intensity, although this approach is based mainly on case reports, increases risk of rejection in patients with organ transplants, and is not always feasible in some patients with hematologic malignancies or primary immunodeficiency syndromes [84–87].

Fig. 1.

Treatment algorithm for progressive multifocal leukoencephalopathy. CPI check point inhibitors, HAART highly active antiretroviral therapy, HIV human immunodeficiency virus, IRIS immune reconstitution inflammatory syndrome, PID primary immunodeficiency, PML progressive multifocal leukoencephalopathy, R/O rule out, VST viral specific T-cell,. *Consider risks of CPI use in solid organ transplant recipients, hematopoietic stem cell transplant recipients, and severe autoimmune disease (see text)

In NZ-PML, plasma exchange (PLEX) is often used in order to remove circulating drugs and to restore immune function. Even though early initiation of PLEX is recommended in some treatment algorithms [88], this recommendation is based on case reports and case series [14, 89, 90]. Immune reconstitution inflammatory syndrome (IRIS), presenting as clinical and radiological exacerbation, has been described following PLEX, more commonly in NZ-PML and HIV patients [14, 89–91]. This syndrome seems to be more common and more severe in patients with natalizumab-associated PML than it is in patients with HIV-associated PML [91]. In addition, recent evidence showed no beneficial effect of PLEX in natalizumab-associated PML with no survival benefit, thus PLEX is no longer recommended [92].

Immune checkpoint inhibitors should be used with caution in patients HSCT recipients, and severe autoimmune disease and SOT recipients due to high rates of rejection and graft failure [93].

Pharmacologic Agents

Several medications have been used to treat PML, although most data come from case reports and case series. The only medications tested in RCT or prospective studies (cidofovir [94], mefloquine [95], cytarabin [96]) did not show benefit. Table 2 summarizes medications that have been used for PML treatment; some are discussed in the text. As this is not a systematic review, a formal methodological appraisal of the included evidence (mostly case reports, case series, and observational studies) was not performed and therefore we cannot determine casuality. In addition, the ability to generalize a consistent efficacy rates is very limited.

Table 2.

Drugs reported to be used as treatment for JCPyV virus infection

Drug	Mechanism of action	Population studied	Study type	Results	Comments
Cytarabine	Anti-neoplastic, anti-metabolite	HIV-associated PML	RCT [96] (n = 57 patients)	Cytarabine administered either intravenously or intrathecally does not improve the prognosis
Mefloquine [95]	Anti-malarial	HIV and non-HIV	Open-label, randomized, parallel-group, proof-of-concept study (37 patients were randomized; only 12 completed the study)	Mefloquine did not show evidence of in vivo antiviral activity, effect on clinical disability, MRI parameters, or survival in comparison with SOC	The study was stopped prematurely because recruitment was slow and an interim analysis suggested that mefloquine failed to reduce JCPyV DNA levels in the cerebrospinal fluid
Cidofovir	Nucleotide analogue	HIV and non HIV		HIV: prospective open label study [94] (n = 24), retrospective multicenter cohort study [185] (n = 35). NZ-PML: Case series [103] (n = 4) and case report [104]	Cidofovir was not associated with improved survival nor improved neurological examination scores in patients with HIV. 3/4 patients with NZ- PML treated with cidofovir or brincidofovir had significant neurological recovery. Brincidofovir lowered JCPyV load in CSF in another patient, but was discontinued due to severe side effects
Topotecan [186]	Topoisomerase inhibitor	AIDS-related PML	Phase 2 clinical trial (n = 11)	3/11 patients showed response to treatment	Topotecan was poorly tolerated; 1 patient died from accidental overdose
Recombinant interleukin 7	Hematopoietic growth factor	HIV and non-HIV	Retrospective cohort study (n = 64) [110]; case reports [107] (see text)	Potential efficacy and good tolerability
Mirtazapine [113]	Antidepressant, alpha-2 antagonist	HIV related PML NZ-PML miscellaneous underlying conditions	5 cohort studies (n = 93), 74 case reports	Few studies reported a potential benefit for mirtazapine, whereas three others found no difference between mirtazapine-treated and untreated patients
Pembrolizumab and nivolumab	Immune check point inhibitors	HIV and non-HIV	Case reports and case series	Some reported benefit [98, 99] (n = 9) while others did not [99]	See text
Filgrastim	Recombinant G-CSF	NZ-PML [105]; fingolimod-associated PML [106]	Retrospective cohort study (n = 17) and case report	Trend towards higher survival rate and favorable neurological outcome
Recombinant interleukin 2 [111]		Patient with follicular lymphoma	Case report	Rapid and sustained clinical improvement

AIDS acquired immunodeficiency syndrome, CSF cerebrospinal fluid, G-CSF granulocyte colony-stimulating factor, HIV human immunodeficiency virus, JCPyV jc polyomavirus, NZ-PML natalizumab associated PML, PML progressive multifocal leukoencephalopathy, RCT randomized control trial, SOC standard of care

Immune checkpoint inhibitors (ICI) have been used to treat PML, based on their mechanism of action enhancing T-cell immune response. Small case series and case reports [52, 97, 98] have reported clinical improvement with ICI in PML patients, but others reported clinical worsening despite treatment [99]. Boumaza et al. [100] collected data on 79 HIV and non-HIV patients who were treated with ICIs as add-on therapy for PML (38 published and 41 unpublished cases). The most used ICI was pembrolizumab, followed by nivolumab. One-year survival remained high, 51.9% (41/79). PML-IRIS was observed in 15 patients (19%), with higher rates among patients with chronic inflammatory diseases and HIV, groups that may achieve immune recovery. The authors suggested a personalized approach while considering ICI therapy for PML. Expression of programmed cell death-1 (PD-1, target site of ICIs on circulating T-cells) before treatment did not differ between survivors and non-survivors in this series.

In a study of cancer patients, the levels of the different lymphocyte subsets was valuable predictive biomarkers of efficacy and clinical prognosis for patients treated with immunotherapy, with a cut-off value of 33.450 for CD4⁺ T-cells [101]. Cortese et al. reported 8 PML patients treated with pembrolizumab. Blood and CSF samples obtained before and after treatment were available for six of the eight patients. Unlike the patients whose PML did not respond to pembrolizumab, those whose PML did respond showed presence of baseline anti-JCPyV-reactive CD4 T-cells, a post-treatment increase in these T-cell reactivity and decline in JCPyV viral load [97].

Cidofovir. Cidofovir inhibits viral replication by incorporating itself into viral DNA, and by inhibiting viral DNA polymerases. In a multicohort analysis [102] of raw data from one prospective and five cohort studies of cidofovir treatment for AIDS-related PML, cidofovir use did not influence PML-related mortality or residual disability. Cidofovir or its lipid conjugate oral analog brincidofovir were used in combination with mirtazapine to treat four patients with NZ-PML [103], all of whom had a decline in CSF viral load, three achieved neurological recovery, and all survived for at least 5 years after PML diagnosis. In another case report, brincidofovir lowered JCPyV load in CSF, but was discontinued due to severe gastrointestinal side effects [104].

Filgrastim. Filgrastim was used as an immune system enhancer in 17 NZ-PML patients in a single center in the US, along with natalizumab discontinuation in all 17, PLEX in 8 patients, maraviroc in 9, mefloquine in 14, and mirtazapine in 15 [105]. The authors’ hypothesis was that filgrastim would increase the number and adhesive properties of T-cell lymphocytes and achieve faster immune recovery. Filgrastim was administered daily until doubling of the baseline lymphocyte count, with a mean duration of 10 days. In this series, 15 patients developed anticipated PML-IRIS, were diagnosed early and treated with steroids. None of the patients died in a follow-up of 2.5 years, seven recovered, and just three had a multiple sclerosis relapse within 1 year. An additional case report described a patient with fingolimod-associated PML, treated with four filgrastim doses after failing mirtazapine. One month after filgrastim treatment completion, the lymphocyte count increased and the patient improved clinically and radiologically without associated IRIS [106].

Recombinant interleukin 7 (rhIL-7). Several case reports [107–109] showed potential efficacy and good tolerability of rhIL7 in non-HIV patients with PML. A 2022 cohort study [110] included 64 patients with PML (27 patients with HIV and 37 with other immunodeficiencies) who received rhIL7. One-year survival was 55% and was associated with > 50% increase in blood lymphocytes and CD4+ T-cells and with > log decrease in CSF JCPyV DNA during the first month after therapy initiation. The type of baseline disease was not associated with mortality.

Recombinant interleukin 2 was used to treat biopsy-proven PML in one patient with follicular lymphoma [111]. The patient improved clinically and radiologically within 2 weeks of interleukin 2 initiation. This improvement occurred along with a decrease in JCPyV viral load and an increase in JCPyV-specific T-cells.

Mirtazapine. The rational for mirtazapine treatment for JCPyV comes from an in vitro study by Atwood et al. [112], who were able to demonstrate that JCPyV employs serotoninergic 5HT- 2A receptors to infect human glial cells. Jamilloux et al. [113] analyzed existing data on mirtazapine’s efficacy to treat PML, and found 74 case reports and 5 cohort studies (167 patients, 93 receiving mirtazapine) published since 2005. In four comparative studies, no significant benefit of mirtazapine was demonstrated, while in one study all the patients received the drug [113]. These included one study in HIV patients, in which a trend toward lower mortality with mirtazapine was reported [114], two studies including natalizumab-associated PML, in which no difference in mortality was found in one [115], while the other study was non-comparative (all patients received mirtazapine and mefloquine and survived) [116]. Two additional studies reported results among patients with various underlying conditions and found no significant benefit of mirtazapine [89, 117]. Because of a low level of evidence, there are no recommendations for the use of mirtazapine in PML treatment. Nevertheless, considering the poor outcomes of PML and the safety profile of the drug, some [113] suggest starting mirtazapine for PML at diagnosis.

Virus Specific Cytotoxic T-Cell

Among the strategies to enhance immune activity against the virus, virus-specific cytotoxic T-cells (CTLs) have been increasingly reported for the treatment of PML [118]. In 2011, Balduzzi et al. [119] presented a case of PML in a 19-year-old male with severe GVHD following allogeneic HSCT. The patient did not improve despite immunosuppression discontinuation and cidofovir therapy. He was treated with JCPyV-specific CTLs with clinical improvement, along with an increase in virus-specific T-cells and a decrease in JCPyV viral load. Another report on successful therapy of three additional PML cases was published a few years later [120]. Various case reports and case series reported 34 cases of PML treated with polyomavirus-specific T-cells [49, 119, 121, 122], [120, 123–126]. These included either BKV- or JCPyV-specific T-cells, and autologous or allogeneic T-cells (from HSCT or third-party donors). Most (23) had hematological malignancy as the underlying disease. Among 32 patients with reported outcomes, 16 improved, 5 stabilized, and 11 continued to deteriorate. A recent series described 28 PML patients who were treated with allogeneic BK polyomavirus-specific T-cells isolated from healthy donors, most of whom had baseline lymphoproliferative disorders. These patients were selected from a larger group of 38 PML patients. Using Enzyme Linked Immunospot (ELISpot) assay to assess for the presence of endogenous BKV/ JCPyV-specific T-cells in peripheral blood, along with clinical considerations, researchers considered patients for either ICI or T-cell therapy. Among the 29 patients treated with T-cell therapy, 22 were classified as treatment response (defined as stable or improved modified Rankin Scale) at 6 months follow-up, and 20 survived beyond 1 year. Adverse events were limited to mild skin reaction in 3 patients. These results were compared to 113 historical controls who were treated with the best supportive therapy and 67 patients treated with ICI, and demonstrated improved survival with specific T-cell therapy [127]. Finally, Mohn et al. published a case series of 28 PML patients, most of them with lymphoproliferative or autoimmune disorder, treated with directly isolated allogeneic virus-specific T-cells, and compared them to historical controls treated with best supportive treatment [127]. In this study, 79% of patients treated with T-cells showed significant clinical stabilization or improvement and a reduction in viral load. Survival analysis showed better 12-month survival rates in the intervention group compared with historical controls. Older age was the only predictor for poor treatment response.

Conclusion

In conclusion, in this review, we have summarized clinical manifestations, risk factors, diagnostic challenges, and management approaches for JCPyV-associated PML, a rare, but often fatal, condition. By synthesizing the existing literature, we offer a treatment algorithm based mainly on underlying immunodeficiency, CD4 cell count, and availability of cellular therapy with viral-specific T-cells. This review underscores the importance of vigilance in at-risk populations and calls for ongoing research to improve outcomes and therapeutic options for PML.

Author Contribution

All authors contributed significantly to the development of this article. Dafna Yahav conceived the study idea and design. Meital Elbaz, Yair Mina and Alaa Atamna collected and analyzed the data. All authors contributed to the interpretation of results and provided critical revisions. All authors participated in drafting the manuscript, reviewed and approved the final version.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflicts of Interest

Meital Elbaz, Yair Mina and Alaa Atamna declare no conflict of interest. Dafna Yahav is an Editorial Board member of Infectious Diseases and Therapy. Dafna Yahav was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.