PML, or progressive multifocal leukoencephalopathy, develops when a common and usually harmless virus called the JC virus reactivates in someone whose immune system is severely weakened. About 61% of healthy adults carry the JC virus without ever knowing it. The virus stays dormant in the kidneys and bone marrow for years or decades, causing no problems at all. PML only happens when something dramatically suppresses the immune system, allowing the virus to travel to the brain and destroy the cells that protect nerve fibers.
The JC Virus and Why It Normally Stays Dormant
Most people pick up the JC virus during childhood or early adulthood through a route that isn’t entirely clear, though it’s thought to spread through contaminated water or respiratory secretions. Seroprevalence rises with age: roughly 60% of adults under 50 carry antibodies against it, climbing to about 65% in those over 50. In a healthy person, the immune system keeps the virus permanently in check. You can carry JC virus your entire life without any symptoms or health consequences.
The critical shift happens when the immune system loses its ability to patrol for the virus. Once surveillance drops below a certain threshold, JC virus can reactivate, enter the bloodstream, and cross into the brain. There, it targets oligodendrocytes, the cells responsible for producing myelin, the insulating coating around nerve fibers. The virus hijacks these cells, replicates inside them, and destroys them. As myelin breaks down in scattered patches across the brain’s white matter, the nerve signals those fibers carry begin to fail. That’s PML.
HIV and AIDS: The Most Common Cause
Before effective HIV treatments existed, PML was one of the more feared complications of AIDS. HIV doesn’t cause PML directly, but it devastates the specific immune cells (CD4 T-cells) responsible for keeping the JC virus dormant. PML in HIV-positive patients is most closely associated with CD4 counts below 100 cells per cubic millimeter, and counts that stay below 50 are associated with fatal cases.
There’s also a more direct link. HIV produces a protein called Tat that can activate the JC virus’s own genetic switches, essentially waking the virus up. So HIV creates a double threat: it strips away immune defenses and simultaneously nudges JC virus toward reactivation. Modern antiretroviral therapy has significantly reduced PML rates among people with HIV, but it remains a risk for those diagnosed late or not receiving treatment.
Medications That Suppress Immunity
Several prescription drugs carry formal FDA black box warnings for PML risk. The most well-known is natalizumab (Tysabri), a medication used to treat multiple sclerosis and Crohn’s disease. Natalizumab works by blocking immune cells from entering the brain, which is exactly what makes it effective for MS but also what creates a blind spot for JC virus.
The risk with natalizumab depends on three factors: whether you carry the JC virus, how long you’ve been on the drug, and whether you’ve previously taken other immune-suppressing medications. For someone who tests positive for JC virus antibodies, has no prior immunosuppressant use, and has been on natalizumab for one to two years, the risk is roughly 0.6 per 1,000 patients. That number climbs substantially with longer use. By four to six years of treatment, it can reach 5 to 6 per 1,000 for patients without prior immunosuppressant exposure, and as high as 10 per 1,000 for those with higher antibody levels and prior immunosuppressant use.
Other medications with black box warnings for PML include rituximab (used for lymphoma, rheumatoid arthritis, and other conditions), mycophenolate mofetil (an anti-rejection drug for organ transplants), and brentuximab vedotin (used for Hodgkin lymphoma). Efalizumab, once used for psoriasis, was removed from the market partly because of PML cases. For most of these drugs, PML risk is considerably lower than with natalizumab, and patients who develop PML while taking them often have additional risk factors like an underlying blood cancer or a history of other immunosuppressive treatments.
Organ and Bone Marrow Transplants
Transplant recipients take powerful immune-suppressing drugs to prevent organ rejection, and this sustained immunosuppression can allow JC virus reactivation. PML was actually first identified in 1958 in three patients with blood cancers, and transplant-related cases continue to occur. Bone marrow transplant recipients face a somewhat earlier window of risk, with a median time of about 11 months from transplant to first PML symptoms. Solid organ transplant recipients typically develop symptoms later, with a median of about 27 months.
Bone marrow transplant patients often receive intensive chemotherapy before the procedure to wipe out their existing marrow, which may compound the risk during the early post-transplant period. Research suggests it’s the transplant process and its accompanying immunosuppression, rather than the underlying disease being treated, that most strongly drives PML risk.
Blood Cancers and Other Immune Disorders
Hematologic malignancies, particularly lymphomas and leukemias, are associated with PML even without transplant involvement. Conditions like chronic lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, and multiple myeloma all appear in PML case reports. These cancers directly disrupt immune cell populations, particularly B-cells and T-cells, creating conditions where JC virus can escape immune surveillance.
More rarely, PML has been reported in people with other conditions that compromise immunity, including certain autoimmune diseases treated with aggressive immunosuppression.
What PML Looks Like When It Develops
PML symptoms depend on where in the brain the virus is active, but they typically build over weeks to months. The most common early signs are progressive weakness on one side of the body, clumsiness, and visual problems. Speech difficulties and personality changes also occur. Because the virus attacks white matter in scattered patches, symptoms can seem unrelated at first, affecting different functions as new areas of the brain become involved.
The lesions most frequently appear in the frontal and parieto-occipital lobes, with the cerebellum, basal ganglia, and brainstem also affected. Notably, the spinal cord and optic nerves are spared. On MRI, PML lesions have a characteristic appearance: sharp borders where they meet the brain’s gray matter but blurred, indistinct edges where they fade into white matter. This pattern reflects how the virus spreads along the small blood vessels that terminate at the boundary between gray and white matter.
How PML Is Diagnosed
Diagnosis relies on a combination of MRI imaging and laboratory testing. On MRI, PML lesions show up brightly on certain sequences, with a distinctive pattern at the expanding edge of each lesion where active viral replication is occurring. The lesion centers, where myelin and nerve fibers have already been destroyed, show a different signal. This “rim-and-core” pattern on diffusion-weighted imaging helps distinguish PML from conditions like multiple sclerosis.
The confirmatory test is a spinal tap to check cerebrospinal fluid for JC virus DNA using an ultrasensitive PCR test. On the initial test, sensitivity is about 85%, meaning it catches most but not all cases. With follow-up testing, sensitivity rises to 95%, and specificity is 100%, meaning a positive result is extremely reliable. A negative first test doesn’t fully rule out PML if the clinical picture is suspicious, which is why repeat testing is sometimes needed.
A Dangerous Complication During Recovery
One of the more paradoxical aspects of PML is that restoring the immune system can temporarily make things worse. When immune function rebounds, whether from starting HIV treatment or stopping an immunosuppressive drug, the newly active immune cells can flood into PML-affected brain areas and cause intense inflammation. This is called PML-IRIS (immune reconstitution inflammatory syndrome), and it causes rapid neurological decline over days to weeks, faster than the trajectory of PML alone.
In HIV patients, PML-IRIS is defined by a rapid worsening of neurological symptoms alongside a doubling of CD4 cell counts and a drop in viral load. On MRI, the key distinguishing feature is patchy, nodular areas of enhancement within existing PML lesions, something seen in about 44% of PML-IRIS cases compared to only 5% in standard PML. PML-IRIS is treatable, but it requires careful management because the inflammation itself can cause significant brain damage.