JC Virus Antibody

JC virus antibody testing detects prior exposure to JC virus, a common polyomavirus that can reactivate and cause life-threatening brain infections in immunosuppressed individuals. 

This serologic marker is critical in assessing the risk of progressive multifocal leukoencephalopathy (PML), particularly in patients treated with natalizumab or other immunomodulatory therapies.

What is JC Virus Antibody?

JC virus (JCV) antibody testing detects the presence of immune system proteins (IgG) formed in response to infection with the JC virus, a common human polyomavirus. Most people are exposed to JCV during childhood and never experience symptoms. 

After initial infection, the virus remains dormant in the kidneys, bone marrow, or lymphoid tissues. JCV can be found in the urine of roughly ⅓ of healthy people.

Antibody production reflects prior exposure, not immunity, and has become a critical biomarker for assessing the risk of JC virus reactivation in immunosuppressed individuals.

JC Virus (JCV) and Antibody Response

The following section details the interaction between the JCV and the immune system:

JC Virus Overview

JCV is typically harmless in healthy individuals, but in people with weakened immune systems, it can reactivate and infect the brain. 

This can lead to progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal demyelinating disease that primarily affects white matter by destroying oligodendrocytes and astrocytes.

Antibody Production

When someone is exposed to JCV, their immune system produces antibodies targeting the virus. 

These antibodies, markers of prior exposure, can be measured in blood using ELISA-based assays. Seroprevalence rates vary widely (30–90%), depending on the population studied.

Clinical Relevance

While the antibodies themselves do not protect against reactivation, their presence helps stratify the risk of PML in patients undergoing immunosuppressive therapy, especially in those treated with natalizumab.

JCV Reactivation and Progressive Multifocal Leukoencephalopathy (PML)

PML is a rare but often fatal demyelinating disease of the central nervous system caused by reactivation of the JC virus in immunocompromised individuals. It primarily affects white matter in the nervous system, leading to progressive neurological decline.

Etiology and Pathogenesis

JCV is a latent polyomavirus in most healthy adults. 

In states of immunosuppression, such as AIDS (particularly with CD4 <200), hematologic malignancy, post-transplantation, or treatment with monoclonal antibodies like natalizumab or rituximab, JCV can reactivate. 

Viral replication in oligodendrocytes leads to lytic destruction of myelin-producing cells, resulting in multifocal demyelinating lesions.

Risk Factors

• HIV/AIDS (especially untreated or with immune reconstitution [PML-IRIS])
• Immunosuppressive therapy (e.g., natalizumab, rituximab)
• Hematologic cancers and solid organ transplantation
• Autoimmune diseases treated with biologics

Clinical Presentation

PML presents subacutely with focal neurological deficits including cognitive decline, motor weakness (e.g., hemiparesis), ataxia, aphasia, and visual disturbances. Symptoms reflect lesion location, typically involving subcortical and periventricular white matter.

Diagnosis

• MRI: Non-enhancing, asymmetric white matter lesions without mass effect; hyperintense on T2-weighted images
• CSF PCR: Detection of JCV DNA confirms diagnosis (though can be negative in PML-IRIS)

Differential diagnosis includes toxoplasmosis, primary CNS lymphoma, HIV encephalopathy, and CMV encephalitis

Management

No curative treatment exists. Management aims to restore immune function:

• HIV/AIDS: Initiate or optimize antiretroviral therapy (ART)
• Immunotherapy-related PML: Discontinue offending agent (e.g., natalizumab), consider plasma exchange
• PML-IRIS: May require corticosteroids to control immune-mediated worsening

Experimental strategies (e.g., dendritic cell vaccines) are under investigation.

Prognosis

Prognosis remains poor, but better outcomes are associated with:

• Low CSF JCV viral load
• Early ART in HIV
• Higher baseline CD4 count
• Strong cytotoxic T-cell response
• Contrast-enhancing lesions on imaging

Clinical Implication

PML should be a key diagnostic consideration in immunocompromised patients with new-onset neurological symptoms. Early detection and immune reconstitution are critical to improving survival.

When is JC Virus Antibody Testing Relevant?

The following scenarios may indicate the need for JCV antibody testing:

Risk Stratification for PML in Immunosuppressed Patients

JC virus antibody testing is primarily used to assess the risk of PML in patients receiving therapies that suppress immune surveillance in the central nervous system. The most notable example is:

• Natalizumab (Tysabri): Used to treat multiple sclerosis (MS) and Crohn’s disease, natalizumab is strongly associated with PML in patients who test positive for JCV antibodies.

Other immunosuppressive agents, such as rituximab and certain chemotherapy drugs, also carry some risk—though typically lower than natalizumab.

Not for Routine Screening

JCV antibody testing is not recommended for the general population. It is specifically used to inform decisions about initiating or continuing immunosuppressive therapy.

Anti-JCV Antibody Testing: Procedure

Anti-JCV antibody testing assesses prior exposure to the JC virus and estimates PML risk in MS patients, particularly those treated with natalizumab. A serum or plasma sample, which is obtained via venipuncture, is often used. 

Results may be determined via a two-step ELISA procedure using JC virus–like particles (VLPs). Results are classified as positive, negative, or indeterminate using predefined cutoffs.

Alternative testing may include quantitative assays, but these may cross-react with BK virus; confirmatory steps are needed for indeterminate results. 

Results Interpretation

Approximately 50–60% of MS patients test positive.

False negative rate: ~2.5%.

In one review, all PML cases in natalizumab-treated patients occurred in those with positive antibody status.

Annual seroconversion rate: ~2% — regular retesting is recommended.

What Do Specific JC Virus Antibody Test Results Mean?

The following results may carry clinical relevance:

Positive Test Result

A positive test result indicates prior infection with JCV. This suggests an increased risk of PML if the patient is receiving natalizumab or similar therapies.

Risk stratification is further refined by:

• Duration of therapy (>24 months)
• History of prior immunosuppressant use
• Antibody index level: an index >1.5 is associated with significantly higher PML risk.

Negative Test Result

Suggests no detectable antibodies, indicating either no prior exposure or antibody levels below detection limits.

Associated with lower—but not zero—risk of PML.

Seroconversion (becoming antibody-positive during treatment) is possible, which is why repeat testing every 6 months is recommended for patients on natalizumab.

What Does the Absence of JC Virus Antibodies Mean?

The absence of JC virus antibodies usually indicates no past infection: in most cases, a negative result reflects a lack of prior exposure to JCV.

However, a negative result does not entirely exclude JCV infection:

• Recent infection may not yet produce detectable antibodies.
• False negatives can occur, especially if the viral load is low or antibody levels are minimal.

Up to 37% of seronegative patients have been found to shed JCV DNA in their urine, indicating prior exposure despite negative serology.