JC Virus

JC virus, named after John Cunningham, is a nonenveloped double-stranded DNA polyomavirus. Primary infection usually occurs in early childhood and is typically mild or subclinical. Following infection, the virus becomes latent and resides in tonsils, renal tubular cells, bone marrow and brain. Seroprevalence studies in adults suggest that approximately 55% of individuals over the age of 20 have been exposed. (Ann Neurol 2015;77:560-70. 

Reactivation of latent virus may cause progressive multifocal leukoencephalopathy (PML) in patients who are immunocompromised or taking immune modulating drugs. PML is a fatal demyelinating disease of the central nervous system.

The preferred test for diagnosis of PML is real time PCR for JC virus in cerebrospinal fluid. PCR should only be ordered for patients with neurological and radiological findings suggestive of PML. PCR is not indicated for screening of asymptomatic patients.

Results are reported as negative or positive. Detection of JC virus DNA supports the clinical diagnosis of progressive multifocal leukoencephalopathy due to JC virus. The lower LoD is 10 DNA copies per microliter of CSF. A negative result does not completely rule out the possibility of JC virus infection. 

Primers are directed to the large T antigen gene, which is a conserved DNA sequence specific for JC virus. PCR does not cross-react with BK virus or Simian Virus 40 (SV40), which are closely related polyomaviruses. Viral culture is not offered by most clinical laboratories. 

Serological tests for anti-JCV antibodies should not be used to diagnose PML since 55% of adults have been exposed to JC virus. A positive result only indicates prior exposure to JC virus.

Natalizumab (Tysabri from Biogen and Tyruko from Sandoz) is a disease modifying therapy for relapsing-remitting multiple sclerosis. Natalizumab therapy is associated with an estimated risk of PML equal to 2.1 cases per 1000 patients treated per year. Testing for JC virus antibody is recommended prior to treatment to determine if a patient is seropositive and, therefore, at higher risk for development of PML. A negative result indicates that an individual has not been exposed to JC virus and is not at risk of developing PML. 

During treatment with Tysabri (Biogen), antibodies against the John Cunningham virus (JCV) are measured with the second-generation STRATIFY JCV DxSelect assay (Focus Diagnostics). During treatment with the biosimilar natalizumab Tyruko (Sandoz), antibodies are measured using the new ImmunoWELL JCV immunoglobulin G (IgG) test (GenBio). Both assays use a 2-step enzyme-linked immunosorbent assay to detect JCV antibodies in serum and calculate index values (index <0.20 is a negative result for both assays, >0.40 is positive for the second-generation assay, and >0.50 is positive for the IgG test). For PML risk assessment using the second-generation assay, an index below 0.9 indicates low PML risk and above 1.5 indicates high PML risk. For the IgG test, PML-risk thresholds were lowered to below 0.8 and above 1.4, respectively.

Specimen requirement for PCR is 0.5 mL of cerebrospinal fluid. Reference value is negative. Specimen requirement for JC virus antibody testing is a red top tube of blood. Reference value is negative. 

References

Gorelik L et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010;68 (3):295-303. 

Lee P, Plavina  T, Castro A,  et al.  A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol. 2013;57(2):141-146.

Adler F, Andersen M, Bartl T,  et al. A new assay for detection of anti-JCV antibodies to support risk stratification and monitoring for progressive multifocal leukoencephalopathy in patients considering or in treatment with natalizumab. Poster presented at the European Committee for Treatment and Research in Multiple Sclerosis Congress; September 18, 2024; Copenhagen, Denmark. Accessed November 25, 2024.

Gelissen LM, et al. Accuracy of New John Cunningham Virus Antibody Assay in Natalizumab-Treated Patients with Multiple Sclerosis. JAMA Neurology, published online March 31, 2025. doi:10.1001/jamaneurol.2025.0337.