Inadequate Immune Humoral Response against JC Virus in Progressive Multifocal Leukoencephalopathy Non-Survivors

Abstract

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization “blind spot” was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients’ humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.

Highly restrictive and directional penetration of the blood cerebral spinal fluid barrier by JCPyV

“…The gold-standard for diagnosis of JC virus induced PML is a positive PCR derived from the CSF using an ultra-sensitive multiplex assay [ 31 , 32 ]. Detection of very low amounts of JCPyV DNA in CSF are used as a diagnostic value for PML (as low as 25 copies/mL), highlighting that even small amounts of infiltrating virus are clinically relevant at the time of diagnosis [ 33 – 35 ]. Monitoring of viral loads and anti-JCPyV antibody levels are also routinely used as methods to determine extended interval dosing schedules in patients taking natalizumab, and assess overall risk [ 36 ].…”

Polyomavirus Wakes Up and Chooses Neurovirulence

“…B cells constitute an important part of the antiviral response, as they are responsible for generating antigen-specific antibodies and are part of immunological memory, which is critical for responding to previously encountered pathogens. In a study following four PML patients, three died within a few months after the onset of PML; the survivor exhibited an increase in neutralizing titers over time in both plasma and CSF, suggesting that the humoral response may be predictive of PML outcome [ 301 ]. Moreover, MS patients with PML exhibited a lack of expansion of B and T cells [ 302 ].…”

B cells going viral in the CNS: Dynamics, complexities, and functions of B cells responding to viral encephalitis

“…Interestingly, PML‐associated JC variants carry mutations promoting virus replication in the CNS 32,33 . PML survival has been associated with the presence of high neutralizing antibody titers in both the plasma and CSF and JC virus‐neutralizing monoclonal antibodies isolated from patients who recovered from PML appear to block virus cell entry 32‐34 . Other CNS infections reported to be linked to anti‐CD20 antibody treatment are enteroviruses and, in isolated cases, HSV and deer tick virus encephalitis 28‐31 .…”

“… 32 , 33 PML survival has been associated with the presence of high neutralizing antibody titers in both the plasma and CSF and JC virus‐neutralizing monoclonal antibodies isolated from patients who recovered from PML appear to block virus cell entry. 32 , 33 , 34 Other CNS infections reported to be linked to anti‐CD20 antibody treatment are enteroviruses and, in isolated cases, HSV and deer tick virus encephalitis. 28 , 29 , 30 , 31 This highlights the need to understand how B cells contribute to suppressing latent and persistent viral infections from entering the CNS or already within the CNS.…”