An Elusive Target: Inhibitors of JC Polyomavirus Infection and Their Development as Therapeutics for the Treatment of Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by infection with JC Polyomavirus (JCPyV). Despite the identification of the disease and isolation of the causative pathogen over fifty years ago, no antiviral treatments or prophylactic vaccines exist. Disease onset is usually associated with immunosuppression, and current treatment guidelines are limited to restoring immune function. This review summarizes the drugs and small molecules that have been shown to inhibit JCPyV infection and spread. Paying attention to historical developments in the field, we discuss key steps of the virus lifecycle and antivirals known to inhibit each event. We review current obstacles in PML drug discovery, including the difficulties associated with compound penetrance into the central nervous system. We also summarize recent findings in our laboratory regarding the potent anti-JCPyV activity of a novel compound that antagonizes the virus-induced signaling events necessary to establish a productive infection. Understanding the current panel of antiviral compounds will help center the field for future drug discovery efforts.

JCV seroconversion rate during the SARS COVID-19 pandemic.

The transmission route of the John Cunningham virus (JCV) is not clearly understood. The high prevalence of JCV in urine and sewage and the stability of the viral particles observed suggest that contaminated water, food, and fomites could be the vehicles of JCV transmission through the oral route. Multiple Sclerosis (MS) patients treated with Natalizumab are at risk of developing progressive multifocal leukoencephalopathy (PML), and hence, JCV serology is monitored for risk stratification. Social restrictions introduced in 2020 which intended to limit the transmission of SARS-CoV-2 are associated with decreased rates of other communicable diseases, as has been shown in recent observational studies. We evaluated the prevalence of seroconversion prior to and during the coronavirus disease (COVID -19) pandemic based on clinical records of JCV serology status in a single-center cohort of Natalizumab-treated Multiple Sclerosis patients. We hypothesized that seroconversion rates would decrease due to behavioral changes. However, seroconversion rates were stable during the COVID-19 pandemic compared to the pre-pandemic. These findings support the notion that JCV is transmitted via the GI tract rather than the respiratory system.

Progressive multifocal leukoencephalopathy in a patient with B-cell chronic lymphocytic leukemia after Covid 19 vaccination, complicated with Covid-19 and mucormycosis: a case report (preprint)

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral demyelinating infectious disease of the central nervous system (CNS) which is rare & fetal. There is various clinical presenting symptoms for the disease. Case presentation: This paper presents a clinical case of PML in a patient with B-CLL in remission, previously treated with Chlorambucil that complicated later in disease course with Covid-19 and mucormycosis. Conclusion: like many other viruses, the more relevant immune-competent cells in host defense against JCV, appear to be T cells. This issue is recently also suggested in Covid 19 patients which a dissociation between severity and seroconversion has been reported. The case reported due to its rarity and multiple challenges in its diagnosis and treatment.

JC virus-induced progressive multifocal leukoencephalopathy in a presumably healthy patient.

BACKGROUND: JC virus (JCV) is common among healthy individuals and remains latent but may be reactivated under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy (PML). Here, we present a rare case of PML caused by JC virus infection in a previously healthy and immunocompetent patient. CASE PRESENTATION: A 67-year-old female without any disease history was admitted after presenting with rapidly progressive dementia. The preoperative diagnosis was progressive multifocal leukoencephalopathy, and corticosteroid treatment did not improve the symptoms. Brain lesions were surgically sampled, and JCV infection was confirmed by high-throughput DNA gene detection. This patient received a combined treatment of mirtazapine, mefloquine, and traditional Chinese herbs, and had stabilization of the disease on followed-up. CONCLUSIONS: Although it is a rare, this case demonstrates that JC virus infection within the brain occurs in apparently healthy people. This case may increase our understanding of virus infection when facing the coronavirus epidemic in recent years, considering that similar medications were used.

[A rare case of multifocal leukoencephalopathy and cerebral stroke after SARS-CoV-2 infection]. / Mul'tifokal'naya leikoentsefalopatiya i ostryi insul't posle infitsirovaniya virusom SARS-CoV-2.

A case of the development of multifocal leukoencephalopathy and hemorrhage after infection with SARS-CoV-2 in a female patient with Alzheimer's disease, aged 67 years, is described. The patient was hospitalized by an ambulance. Computed tomography (CT) of the brain showed the signs of cerebral infarction in the basin of the left middle cerebral artery with hemorrhagic transformation, multiple low-density foci that do not accumulate contrast in the white matter of the brain, the presence of sickle-shaped lesions in the cerebellum. CT of the chest revealed bilateral diffuse COVID-associated pneumonitis, alveolitis. The percentage of lesion was 75%. A smear express test for a new coronavirus infection was positive. Treatment was started, and a sudden death occurred. A sectional study in the brain revealed signs of ischemic cerebral infarction and multifocal leukoencephalomalacia - foci of demyelination (from 1 mm to 1 cm) had a multifocal lesion located in different parts of the white matter. Fibrinoid necrosis of vessel walls, destructive-productive vasculitis, ischemic small-focal perivascular necrosis, ischemic lesions of neurons and glial cells, neuronal and glial spongiosis were noted. In conclusion, the cause of death of the patient was a new coronavirus infection COVID-19, which caused diffuse viral COVID-associated pneumonitis, alveolitis with the development of acute respiratory distress syndrome in adults, respiratory failure and COVID-associated ischemic infarction, multifocal leukoencephalopathy (or malacia), cerebral edema complicated by neuromorphological changes in the brain.

Progressive multifocal leukoencephalopathy in an immunocompetent patient: A case report and review of literature.

Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain, caused by the John Cunningham virus (JCV) is usually seen in patients who are immunocompromised. Here, we describe a case of an immunocompetent patient diagnosed with PML and a comprehensive literature review. A 64-year-old Caucasian male presented with acute worsening of progressive neurological decline with difficulty in vision and reading. Based on history, examination, cerebrospinal fluid markers, histopathology, and magnetic resonance imaging brain at the time of presentation diagnosed the patient with PML in a setting of no immunosuppression disorder. The patient was started on Pelfilgrastim with significant systematic improvement. In our literature review, it was seen that the average age of symptom presentation was 57.5 with predominance in males. Most of the patients presented with progressive neurological deficits with symptomology ranging from mild confusion, aphasia, anxiety to sensory disturbances with numbness, hemiparesis, and hemianopsia. Out of the 21 cases, patients responded to mirtazapine and intravenous pulse methylprednisolone (IVMP). The mortality rate was close to 50% with 11 fatal cases and 10 nonfatal cases. Our case and literature review demonstrate the possibility that PML may very rarely occur in patients that are immunocompetent. Furthermore, our review showed that patients responded well to mirtazapine and IVMP. We also want to highlight that the mortality rate was lower in this review and was only compared to mortality in PML associated with immunocompromised status.

Wearing-off symptoms during standard and extended natalizumab dosing intervals: Experiences from the COVID-19 pandemic.

Natalizumab effectively prevents disease activity in relapsing-remitting multiple sclerosis, but many treated patients report subjective wearing-off symptoms at the end of the 4-week interval between infusions. Extended interval dosing (EID) is a promising strategy to mitigate the risk of natalizumab-associated progressive multifocal leukoencephalopathy, but it is unknown whether EID affects wearing-off symptoms. In this observational study, we evaluated if prevalence or intensity of wearing-off symptoms changed when natalizumab dosing intervals were extended from 4 to 6 weeks in 30 treated patients during the outbreak of COVID-19 in Norway. New or increased wearing-off symptoms during EID were reported by 50%. Symptom increase was more frequent among patients with pre-existing wearing-off symptoms during standard dosing compared to patients without such pre-existing symptoms [p = 0.0005]. Our observations support the need to study the effect of EID on wearing-off symptoms in randomized controlled trials.

Unexpected worsening of progressive multifocal leucoencephalopathy following COVID-19 pneumonia.

Progressive multifocal leucoencephalopathy is a serious side effect of natalizumab, a humanized monoclonal antibody approved for the treatment of multiple sclerosis. Here, we report a case of unexpected worsening of natalizumab-related progressive multifocal leucoencephalopathy following COVID-19. After natalizumab discontinuation, a slight neurological improvement was observed, but, two months later the patient was admitted to the hospital because of neurological deterioration and COVID-19 mild pneumonia. Except for SARS-CoV-2 infection, no other potential factors of neurological worsening were identified. Thus, we pose the hypothesis that SARS-CoV-2 was instrumental in the progressive multifocal leucoencephalopathy deterioration.

Biological Significance of Anti-SARS-CoV-2 Antibodies: Lessons Learned From Progressive Multifocal Leukoencephalopathy.

OBJECTIVE: To discuss the pathogenic and diagnostic relevance of cellular and humoral immune responses against severe acute respiratory syndrome novel coronavirus (SARS-COV-2) and pertinent observations made in progressive multifocal leukoencephalopathy (PML). METHODS: Review of pertinent literature. RESULTS: There is at least 1 precedent for an antibody response against a viral pathogen that fails to provide host protection in the absence of immune-competent CD4+ T cells. PML is an infection of the CNS caused by JC virus (JCV), which commonly occurs during treatment with the therapeutic monoclonal antibody natalizumab. In this context, the humoral immune response fails to prevent JCV reactivation, and elevated anti-JCV serum indices are associated with a higher PML incidence. The more relevant immune-competent cells in host defense against JCV appear to be T cells. T cell-mediated responses are also detectable in convalescing patients with SARS-COV-2 irrespective of the humoral immune response. CONCLUSION: Based on pathogenic lessons learned from PML under natalizumab therapy, we suggest the incorporation of functional assays that determine neutralizing properties of SARS-CoV-2-specific antibodies. In addition, we outline the potential role of T-cell detection assays in determining herd immunity in a given population or in studying therapeutic responses to vaccines.