Among the three established risk factors for progression to PML during natalizumab treatment (AI, treatment duration, prior immunosuppressant use) (Plavina et al.
2014; McGuigan et al.
2015), AI has been used to determine which patients should initiate natalizumab therapy and at what point a patient should be transitioned to alternatives. Given that PML cases have continued to increase with only a modest reduction since antibody titer/AI measurements were introduced (Fig.
1) (
www.biogen.com), augmenting risk algorithms with additional risk factors seems imperative. The prevalence of JCV viruria among natalizumab-treated patients is reported to cover a wide range (18–87 %) (Delbue et al.
2015; Lanzillo et al.
2014; Laroni et al.
2012; Bellizzi et al.
2013; Rinaldi et al.
2010), but no association between viruria prevalence and progression to PML has been found. The strong correlation demonstrated herein between AI and JCV viruria indicates that natalizumab-treated patients with active JCV infection commonly fall into a high-risk category for progression to clinical disease (Plavina et al.
2014). Ferrante and co-workers made a similar observation, finding that more than 80 % of patients with viruria were also seropositive for JCV-specific antibodies, but could not assign these observations to low or high PML risk groups since the AI had not yet been introduced into clinical practice (Delbue et al.
2015). For this reason, measurement of urinary excretion has not accompanied analysis of AI in PML cases either. It had been previously concluded that viruria is not correlated with serostatus or antibody titer in PML cases (Rudick et al.
2010) and not even the prevalence of JCV excretion in PML cases has been systematically measured. The clear correlation between AI and viruria reported herein should force re-examination of this issue in PML cases.
The introduction of new handling procedures for patient urine has resulted in consistent measurement of patient viral loads for genitourinary virus. These methods may overcome the reported observation that JCV viruria is intermittent (see Clausi et al.
2015; Delbue et al.
2015; Lanzillo et al.
2014; Domínguez-Mozo et al.
2013; Saundh et al.
2010 for examples). The introduction of DNAse and chemical treatments suggests that actual, encapsidated virus can now be quantified in patient samples. Intermittent excretion made the measure of urinary JCV of little diagnostic benefit, leaving it largely ignored in the approach to mitigating PML risk. Given that appropriate interrogation of the urine reveals a consistent signal that likely represents encapsidated virus, that the viral load is high and strongly correlated with high antibody titer, and the fact that the level of viruria increases with progression to PML (Delbue et al.
2015; Bellizzi et al.
2013; Domínguez-Mozo et al.
2015) suggest urinary JCV has clinical value. Active JCV infection in the urine can often be detected prior to JCV antibodies (Laroni et al.
2012; Lanzillo et al.
2014), directing attention to those patients that may already be heading down the path to neurotropic JCV. The conundrum has always been where the transformation from genitourinary (i.e., archetype) to neurotropic JCV takes place. Correlation between the site(s) of viral replication, the prevalence of viral excretion, the level of viral replication, and the antibody titer/index, as described herein, may point the finger at the primary JCV reservoir as the site of origin for neurotropic JCV, but whose independence from the reservoir is established after initial escape (Reid et al.
2011; Van Loy et al.
2015). Consistent with this hypothesis, genomic rearrangements and VP1 capsid mutations, both implicated in enabling virus to migrate into other tissues and organs, have only been identified from plasma or serum, PBMC subsets, and PML brain or cerebrospinal fluid (CSF) (Reid et al.
2011; Gorelik et al.
2011). PML remains rare, a consequence of the rarity of events necessary to enable JCV mobilization and migration during natalizumab treatment. The selective pressure to mutate will increase for the virus once it leaves its traditional replicative milieu, driving the types of transformations that have now been documented in both coding and non-coding regions of the viral genome. But therapeutic intervention may best be focused at the origin of these events and along the path leading to the CNS. With the ability to directly measure patient viral load from an accessible compartment now established, a biomarker exists from which the response to antiviral therapy can begin to be measured in natalizumab patients.