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The cause of PML is a type of polyomavirus called the JC virus (JCV), after the initials of the patient from whose tissue the virus was first successfully cultured. Recent publications indicate 39% to 58% of the general population are seropositive for antibodies to JCV, indicating current or previous infection with virus.

The JC virus or John Cunningham virus (JCV) is a type of human polyomavirus (formerly known as papovavirus) and is genetically similar to BK virus and SV40. It was discovered in 1965 by ZuRhein and Chou and by Silverman and Rubinstein and later named using the two initials of a patient with progressive multifocal leukoencephalopathy (PML). The virus is very common in the general population, infecting 70 to 90 percent of humans; most people acquire JCV in childhood or adolescence. It is found in high concentrations in urban sewage worldwide, leading some researchers to suspect contaminated water as a typical route of infection.

Minor genetic variations are found consistently in different geographic areas; thus, genetic analysis of JC virus samples has been useful in tracing the history of human migration. 14 subtypes or genotypes are recognized each associated with a specific geographical region. Three are found in Europe (a, b and c). A minor African type—Af1—occurs in Central and West Africa. The major African type—Af2—is found throughout Africa and also in West and South Asia. Several Asian types are recognised B1-a, B1-b, B1-d, B2, CY, MY and SC.

An alternative numbering scheme numbers the genotypes 1–8 with additional lettering. Types 1 and 4 are found in Europe and in indigenous populations in northern Japan, North-East Siberia and northern Canada. These two types are closely related. Types 3 and 6 are found in sub-Saharan Africa: type 3 was isolated in Ethiopia, Tanzania and South Africa. Type 6 is found in Ghana. Both types are also found in the Biaka Pygmies and Bantus from Central Africa. Type 2 has several variants: subtype 2A is found mainly in the Japanese population and native Americans (excluding Inuit); 2B is found in Eurasians; 2D is found in Indians and 2E is found in Australians and western Pacific populations. Subtype 7A is found in southern China and South-East Asia. Subtype 7B is found in northern China, Mongolia and Japan Subtype 7C is found in northern and southern China. Subtype 8 is found in Papua New Guinea and the Pacific Islands.

The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with drugs intended to induce a state of immunosuppression (e.g., organ transplant patients).The virus can cause persistent asymptomatic infection in approximately one-third of the adult population, based on viral shedding into the urine from the site of asymptomatic infection in the kidney. The virus causes disease only when the immune system has been severely weakened.

Prior to the advent of effective antiretroviral therapy, as many as 5% of people with AIDS eventually developed PML. It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects.

The initial site of infection may be the tonsils, or possibly the gastrointestinal tract. The virus then remains latent in the gastrointestinal tract and can also infect the tubular epithelial cells in the kidneys, where it continues to reproduce, shedding virus particles in the urine.

JCV can cross the blood–brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT2A serotonin receptor. JC viral DNA can be detected in both non-PML affected and PML-affected (see below) brain tissue.

Immunodeficiency or immunosuppression allows JCV to reactivate. In the brain it causes the usually fatal progressive multifocal leukoencephalopathy, or PML, by destroying oligodendrocytes. Whether this represents the reactivation of JCV within the CNS or seeding of newly reactivated JCV via blood or lymphatics is unknown. Several studies since 2000 have suggested that the virus is also linked to colorectal cancer, as JCV has been found in malignant colon tumors, but these findings are still controversial.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS characterized by widespread lesions due to infection of oligodendrocytes by a human papovavirus. The virus was identified as the etiological agent in 1967 and is named JC virus in 1971 after John Cunningham, from whom it was first isolated. It occurs almost exclusively in immunosuppressed individuals, such as patients with AIDS, hematological and lymphoreticular malignancies, autoimmune rheumatological diseases, or those undergoing organ transplantation.

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PML has also been reported in patients receiving immune therapy with monoclonal antibodies (eg, natalizumab, rituximab) and various other immunosuppressants, including prednisone, cyclophosphamide, methotrexate, and cyclosporine.

PML is associated with both HIV-1 and HIV-2. HIV infection accounts for almost 85% of the total cases, and its prevalence in this population is around 4-5%. It is currently one of the AIDS-defining illnesses in HIV-infected patients.

HIV-associated PML also occurs during immune recovery following the initiation of highly active antiretroviral therapy (HAART). Such cases are associated with an inflammatory reaction in brain lesions and contrast enhancement on neuroimaging studies. The outcome of inflammatory PML is more variable than that of PML in end-stage AIDS.

Most patients with HIV infection develop PML in the setting of a poor immunological status expressed by a low CD4 cell count (< 200/µL). Very few reports have described of PML in HIV-infected patients in the setting of better immunological function (ie, CD4 counts >500/µL).

Drugs associated with reactivation

Since immunodeficiency causes this virus to progress to PML, immunosuppressants are contraindicative to those infected.

The boxed warning for the drug Rituximab (Rituxan, co-marketed by Genentech BioOncology and Biogen Idec) includes a statement that JC virus infection resulting in progressive multifocal leukoencephalopathy, and death has been reported in patients treated with the drug.

The boxed warning for the drug natalizumab (Tysabri, marketed by Elan and developed by Biogen Idec) includes a statement that JC virus resulted in progressive multifocal leukoencephalopathy developing in three patients who received natalizumab in clinical trials.

The boxed warning was added on Feb. 19, 2009, for the drug efalizumab (Raptiva, marketed in the U.S. by Genentech, and marketed in Europe by Swiss drugmaker Merck Serono) includes a statement that JC virus, resulting in progressive multifocal leukoencephalopathy, developed in three patients who received efalizumab in clinical trials. The drug was pulled off the U.S. market because of the association with PML on April 10, 2009.

A boxed warning for brentuximab vedotin (Adcetris) was issued by the FDA on January 13, 2011 after two cases of PML were reported, bringing the total number of associated cases to three.

Treatments

In June 2010, the first case report appeared of a PML patient being successfully treated with mefloquine. Mefloquine is an antimalarial drug that can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patient’s body and prevented further neurological deterioration. A further trial lead to non significant results between standard of care arm and mefloquine arm. This study found no evidence of anti-JCV activity by mefloquine.

On November 30, 2010, Cytheris announced that they had eradicated the JC virus from a PML patient, using their human interleukin-7 investigational drug (CYT107) combined with Chimerix’s investigational, orally-available lipid conjugate prodrug of Cidofovir (CMX001). However, this therapy was attempted only once and further studies are needed to determine if this is a viable alternative.

Cases have been reported of PML being caused by pharmacological agents, although this could be due in part to the existing impaired immune response or ‘drug combination therapies’ rather than individual drugs. These include: Efalizumab, Belatacept, Rituximab, Natalizumab, Infliximab chemotherapy, corticosteroids, and various transplant drugs such as tacrolimus.

PML is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the subcortical white matter, particularly that of the parietal and occipital lobes. PML destroys oligodendrocytes and produces intranuclear inclusions. PML is similar to another demyelinating disease, multiple sclerosis, but progresses much more quickly. Progression is quick and the breakdown of myelin is commensurate with the level of immuno-compromisation.

Symptoms

Symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration.

In addition, the lesions affecting the parietal and occipital lobes can lead to a phenomenon known as alien hand syndrome.

PML is diagnosed by testing for JC virus DNA in cerebrospinal fluid or in a brain biopsy specimen. Characteristic evidence of the damage caused by PML in the brain can also be detected on MRI images, which classically show multifocal nonenhancing lesions without mass effect. The most common area of involvement is the cortical white matter, but the brainstem and cerebellum may also be involved.

There is no known cure. In some cases, the disease slows or stops if the patient’s immune system improves; some AIDS patients with PML have been able to survive for several years, with the advent of highly active antiretroviral therapy (HAART).

AIDS patients who start HAART after being diagnosed with PML tend to have a slightly longer survival time than patients who were already on HAART and then develop PML. A rare complication of effective HAART is immune reconstitution inflammatory syndrome (IRIS), in which increased immune system activity actually increases the damage caused by the infection; although IRIS is often manageable with other types of drugs, it is extremely dangerous if it occurs in PML.

Other antiviral agents that have been studied as possible treatments for PML include cidofovir and interleukin-2, but this research is still preliminary.

Cytarabine (also known as ARA-C), a chemotherapy drug used to treat certain cancers, has been prescribed on an experimental basis for a small number of non-AIDS PML patients. It is reported to have stabilized the neurological condition of a minority of these patients. One patient regained some cognitive function lost as a result of PML.

In June 2010, the first case report appeared of a PML patient being successfully treated with Mefloquine. Mefloquine is an antimalarial drug that can also act against the JC virus. Administration of Mefloquine seemed to eliminate the virus from the patient’s body and prevented further neurological deterioration.

Reginald Todd Hewitt, after losing his daughter to PML (and misdiagnosis) decided to Take Action and fight for a cure. Research on this disease must be addressed globally, and below is the beginning of a new movement to make this happen.

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Since Courtney’s death in 2009 of Progressive Multifocal Leukoencephalopathy, TCP (The Courtney Project 501 c3) founded by her father, Reginald Todd Hewitt has established numerous PML Awareness Chapters across the United States has received much deserved recognition by many local and state officials including Congresswoman Corrine Brown, Governors of Florida, South Carolina, Georgia, North Carolina, Tennessee, Oregon, Alabama and Texas.

“When PML claimed my daughter Courtney’s life, I thought to myself, how can one person could possibly accomplish such a huge task?

I began my personal quest to raise Worldwide Awareness!”

PML itself is caused from the JC Virus, which is lying dormant in 85 to 90% of our World’s Population!!

2014 being the 5th Anniversary of Courtney’s death, we ask that everyone reading this feature, help today!

In today’s society there are many definitions of a Modern Family. This family (Reginald and his life partner Hubert of 32 plus years) their three daughters (Chloe’, Kylie Claudia) and one son (Alex) certainly ranks right up their with the best of them!

Reginald Todd Hewitt,

The Courtney Project 501c3
117 North Kirkman Road
Orlando, Florida 32811
321-388-1952
407-291-8658
Fax: 407-291-8890

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