Progressive multifocal leukoencephalopathy

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Progressive multifocal leukoencephalopathy
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T2-weighted MRI showing progressive multifocal leukoencephalopathy
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Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal). It is caused by the JC virus, which is normally present and kept under control by the immune system. The JC virus is harmless except in cases of weakened immune systems. In general, PML has a mortality rate of 30–50% in the first few months, and those who survive can be left with varying degrees of neurological disabilities.

Contents

PML occurs almost exclusively in patients with severe immune deficiency, most commonly among patients with acquired immune deficiency syndrome (AIDS), but people on chronic immunosuppressive medications including chemotherapy are also at increased risk of PML, such as patients with transplants, Hodgkin's lymphoma, multiple sclerosis, psoriasis, rheumatoid arthritis, and other autoimmune diseases.

Signs and symptoms

Symptoms can develop over several weeks to months, and they depend on location of damage in the brain and the degree of damage. The most prominent symptoms are "clumsiness, progressive weakness, and visual, speech, and sometimes personality changes". [1] The lesions affecting the parietal and occipital lobes of the brain can lead to a phenomenon known as alien hand syndrome. [2]

Cause

JC virus infection

The cause of PML is a type of polyomavirus called the JC virus (JCV), after the initials of the person (John Cunningham) from whose tissue the virus was first successfully cultured. Publications indicate 39 [3] to 58% [4] of the general population are seropositive for antibodies to JCV, indicating current or previous infection with the virus. Other publications put the percentage at 70 to 90% of the general population. [5] JCV causes persistent asymptomatic infection in about 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. [6]

Immunosuppression

PML is most common in people with HIV1 infection; prior to the advent of effective antiretroviral therapy, as many as 5% of people with AIDS eventually developed PML. [1] Why PML occurs more frequently in people with AIDS than in other immunosuppressive conditions is unclear; 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. [7]

PML can still occur in people on immunosuppressive therapy, such as efalizumab, belatacept, and various transplant drugs, which are meant to weaken the immune system. [8]

Multiple sclerosis medications

Natalizumab (Tysabri) was approved in 2004 by the FDA for the treatment of multiple sclerosis (MS). It supposedly works by preventing white blood cells from entering the brain. It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of PML. [8] All three initial cases were taking natalizumab in combination with interferon beta-1a. [8] After a safety review, the drug was returned to the market in 2006 as a monotherapy for MS under a special prescription program. [8] As of May 2011, over 130 cases of PML had been reported in MS patients, all in patients who had taken natalizumab for more than a year. [8] While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between three- and four-fold. [8] The estimated prevalence of PML in MS is 1.5 cases per thousand natalizumab users. [8] Around 20% of MS patients with PML die, and most of the rest are very disabled. [8] One case study describes an MS patient who, during a 4-year course of dimethyl fumarate, developed PML and died. [9]

Fingolimod (Gilenya) was approved in 2010 by the FDA for MS. In 2015, the first case of PML and a case of "probable PML" were reported by two Gilenya users that could not be tied to previous immunosuppressant therapies. These new cases are now being added to the drug information sheet included with every prescription (i.e. the "drug label"). [10]

Pathogenesis

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. It is similar to another demyelinating disease, MS, but progresses much more quickly. The breakdown of myelin is proportional to the degree of immunocompromise. [11]

Diagnosis

PML is diagnosed in a patient with a progressive course of the disease, finding JC virus DNA in spinal fluid together with consistent white-matter lesions on brain magnetic resonance imaging (MRI); alternatively, a brain biopsy is diagnostic [1] when the typical histopathology of demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei are present, coupled with techniques showing the presence of JC virus. [12]

Characteristic evidence of PML on brain CT scan images are multifocal, noncontrast enhancing hypodense lesions without mass effect, but MRI is far more sensitive than CT. [12] The most common area of involvement is the cortical white matter of frontal and parieto occipital lobes, but lesions may occur anywhere in the brain, such as the basal ganglia, external capsule, and posterior cranial fossa structures such as the brain stem and cerebellum. [12] Although typically multifocal, natalizumab-associated PML is often monofocal, predominantly in the frontal lobe. [12]

Treatment

No drugs effectively inhibit or cure the virus infection without toxicity. Therefore, treatment aims at reversing the immune deficiency to slow or stop the disease progress. In patients on immunosuppression, this means stopping the drugs or using plasma exchange to accelerate the removal of the biologic agent that put the person at risk for PML. [1]

In HIV-infected people, this may mean starting highly active antiretroviral therapy (HAART). AIDS patients starting 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. [13] Some AIDS patients with PML have been able to survive for several years, with HAART. [14] 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 JCV infection; although IRIS can often be managed with medication, it is extremely dangerous in PML. [15]

Cidofovir was studied as possible treatment for PML [16] and has been used on a case-by-case basis, working in some, but not others.

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, and stabilized the neurological condition of a minority of these patients. [17] One patient regained some cognitive function lost as a result of PML. [18]

In June 2010, the first case report appeared of a PML patient being successfully treated with the antimalarial drug mefloquine with activity against the JC virus. The patient cleared the virus and had no further neurological deterioration. [19] Two case reports of using interleukin-2 successfully have been published. [20] Some success have been reported with mirtazapine, but this has not been demonstrated in clinical trials. [21] A number of drugs work against JC virus in cell culture, but no proven, effective therapy is known in humans. [22] For example, Brincidofovir (1-O-hexadecyloxypropyl-cidofovir /CMX001) available as Tembexa, suppresses JCV, [23] but has been found to have toxicity at therapeutic dosage. [24] Infusion of donor T cells specific to the related BK polyomavirus has shown possible effect in treating PML in one small study by Katy Rezvani's group, but needs further study. [25] In December 2021, Cellevolve announced it is launching a clinical trial for the treatment of PML utilizing BK virus specific T-cells (VSTs). [26]

Prognosis

One-third to one-half of people with PML die in the first few months following diagnosis, depending on the severity of their underlying disease. Survivors can be left with variable degrees of neurological disability. [1]

See also

Related Research Articles

<i>Polyomaviridae</i> Family of viruses

Polyomaviridae is a family of viruses whose natural hosts are primarily mammals and birds. As of 2020, there are six recognized genera and 117 species, five of which are unassigned to a genus. 14 species are known to infect humans, while others, such as Simian Virus 40, have been identified in humans to a lesser extent. Most of these viruses are very common and typically asymptomatic in most human populations studied. BK virus is associated with nephropathy in renal transplant and non-renal solid organ transplant patients, JC virus with progressive multifocal leukoencephalopathy, and Merkel cell virus with Merkel cell cancer.

<i>Human polyomavirus 2</i> Species of virus

Human polyomavirus 2, commonly referred to as the JC virus or John Cunningham virus, is a type of human polyomavirus. It was identified by electron microscopy in 1965 by ZuRhein and Chou, and by Silverman and Rubinstein, and later isolated in culture and named using the two initials of a patient, John Cunningham, with progressive multifocal leukoencephalopathy (PML). The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with immunosuppressive drugs.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

<span class="mw-page-title-main">Cidofovir</span> Antiviral drug

Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis in people with AIDS.

<span class="mw-page-title-main">Fingolimod</span> Chemical compound

Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, used for the treatment of multiple sclerosis. Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction. It has been reported to reduce the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period.

<span class="mw-page-title-main">Opportunistic infection</span> Infection caused by pathogens that take advantage of an opportunity not normally available

An opportunistic infection is an infection caused by pathogens that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune system, an altered microbiome, or breached integumentary barriers. Many of these pathogens do not necessarily cause disease in a healthy host that has a non-compromised immune system, and can, in some cases, act as commensals until the balance of the immune system is disrupted. Opportunistic infections can also be attributed to pathogens which cause mild illness in healthy individuals but lead to more serious illness when given the opportunity to take advantage of an immunocompromised host.

<span class="mw-page-title-main">Natalizumab</span> Medication used to treat multiple sclerosis and Crohns disease

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenous infusion. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.

HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during the late stages of the disease, when immunodeficiency is severe. HAND may include neurological disorders of various severity. HIV-associated neurocognitive disorders are associated with a metabolic encephalopathy induced by HIV infection and fueled by immune activation of macrophages and microglia. These cells are actively infected with HIV and secrete neurotoxins of both host and viral origin. The essential features of HIV-associated dementia (HAD) are disabling cognitive impairment accompanied by motor dysfunction, speech problems and behavioral change. Cognitive impairment is characterised by mental slowness, trouble with memory and poor concentration. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioral changes may include apathy, lethargy and diminished emotional responses and spontaneity. Histopathologically, it is identified by the infiltration of monocytes and macrophages into the central nervous system (CNS), gliosis, pallor of myelin sheaths, abnormalities of dendritic processes and neuronal loss.

Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of HIV/AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.

<span class="mw-page-title-main">BK virus</span> Member of the polyomavirus family

The BK virus, also known as Human polyomavirus 1, is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed. BK virus is an abbreviation of the name of the first patient, from whom the virus was isolated in 1971.

Efalizumab is a formerly available medication designed to treat autoimmune diseases, originally marketed to treat psoriasis. As implied by the suffix -zumab, it is a recombinant humanized monoclonal antibody administered once weekly by subcutaneous injection. Efalizumab binds to the CD11a subunit of lymphocyte function-associated antigen 1 and acts as an immunosuppressant by inhibiting lymphocyte activation and cell migration out of blood vessels into tissues. Efalizumab was associated with fatal brain infections and was withdrawn from the market in 2009.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). Several therapies for it exist, although there is no known cure.

<span class="mw-page-title-main">Decoy cells</span> Virally infected epithelial cells found in urine

Decoy cells are virally infected epithelial cells that can be found in the urine. Decoy cells owe their name to their strong resemblance to cancer cells, and may as such confuse the diagnosis of either viral infection or urothelial malignancy. During 1950s, cytotechnologist Andrew Ricci observed cells mimicking cancer cells by they were not, in a group of persons working in some kinds of industries - they were referred to as “decoy cells”, analogous to “decoy ducks” used in hunting wild ducks, by Andrew Ricci, a cytotechnologist working renown cytopathologist Dr. Leopold G. Koss.

The central nervous system (CNS) controls most of the functions of the body and mind. It comprises the brain, spinal cord and the nerve fibers that branch off to all parts of the body. The CNS viral diseases are caused by viruses that attack the CNS. Existing and emerging viral CNS infections are major sources of human morbidity and mortality.

Neurovirology is an interdisciplinary field which represents a melding of clinical neuroscience, virology, immunology, and molecular biology. The main focus of the field is to study viruses capable of infecting the nervous system. In addition to this, the field studies the use of viruses to trace neuroanatomical pathways, for gene therapy, and to eliminate detrimental populations of neural cells.

Eugene O. "Gene" Major is a senior investigator at the National Institute of Neurological Disorders and Stroke (NINDS), a part of the United States National Institutes of Health (NIH). Major conducts research into the neurological diseases including progressive multifocal leukoencephalopathy (PML), caused by JC virus and often found in immunosuppressed patients such as those with HIV/AIDS. Major has published over 140 scientific articles and reviews in the peer-reviewed literature and has contributed to Fields Virology, a standard virology textbook.

Joseph R. Berger is an American internist and neurologist who is known for his research interests in progressive multifocal leukoencephalopathy (PML), the neurological complications of HIV/AIDS, multiple sclerosis, and other inflammatory disorders of the brain. Particularly, he contributed research on why PML occurs more frequently in AIDS than in other immunosuppressive conditions.

<span class="mw-page-title-main">Signs and symptoms of HIV/AIDS</span>

The stages of HIV infection are acute infection, latency, and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, swollen lymph nodes, inflammation of the throat, rash, muscle pain, malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts, various opportunistic infections, cancers, and other conditions.

<span class="mw-page-title-main">Agnoprotein</span> Viral protein found in some polyomaviruses

Agnoprotein is a protein expressed by some members of the polyomavirus family from a gene called the agnogene. Polyomaviruses in which it occurs include two human polyomaviruses associated with disease, BK virus and JC virus, as well as the simian polyomavirus SV40.

Igor Koralnik is an American physician, neurologist and scientist. He is one of the first physicians to study the neurologic complications caused by the human immunodeficiency virus (HIV) and is a leading researcher in the investigation of the polyomavirus JC, which causes progressive multifocal leukoencephalopathy (PML), a disease of the central nervous system that occurs in immunosuppressed individuals.

References

  1. 1 2 3 4 5 "Progressive Multifocal Leukoencephalopathy Information Page". National Institute of Neurological Disorders and Stroke. National Institutes of Health. 14 February 2014. Retrieved 11 September 2020.
  2. ↑ Panikkath, Ragesh; Panikkath, Deepa; Mojumder, Deb; Nugent, Kenneth (2014). "The alien hand syndrome". Proceedings (Baylor University. Medical Center). 27 (3): 219–220. doi:10.1080/08998280.2014.11929115. PMC   4059570 . PMID   24982566.
  3. ↑ Kean, Jaime M.; Rao, Suchitra; Wang, Michael; Garcea, Robert L. (2009). Atwood, Walter J. (ed.). "Seroepidemiology of Human Polyomaviruses". PLOS Pathogens. 5 (3): e1000363. doi: 10.1371/journal.ppat.1000363 . PMC   2655709 . PMID   19325891.
  4. ↑ Egli, Adrian; Infanti, Laura; Dumoulin, Alexis; Buser, Andreas; Samaridis, Jacqueline; Stebler, Christine; Gosert, Rainer; Hirsch, Hans H. (2009). "Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors". The Journal of Infectious Diseases. 199 (6): 837–46. doi: 10.1086/597126 . PMID   19434930.
  5. ↑ Laura A. Shackelton; Andrew Rambaut; Oliver G. Pybus; Edward C. Holmes (2006). "JC Virus evolution and its association with human populations". Journal of Virology. 80 (20): 9928–9933. doi:10.1128/JVI.00441-06. PMC   1617318 . PMID   17005670.
  6. ↑ Cortese, Irene; Reich, Daniel S.; Nath, Avindra (January 2021). "Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease". Nature Reviews Neurology. 17 (1): 37–51. doi:10.1038/s41582-020-00427-y. ISSN   1759-4766. PMC   7678594 . PMID   33219338.
  7. ↑ Berger, Joseph (2003). "Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome: explaining the high incidence and disproportionate frequency of the illness relative to other immunosuppressive conditions". J. Neurovirol. 9 Suppl 1 (2): 38–41. doi:10.1080/13550280390195261. PMID   12709870. S2CID   17171153.
  8. 1 2 3 4 5 6 7 8 Kappos, Ludwig; Bates, David; Edan, Gilles; Eraksoy, Mefkûre; Garcia-Merino, Antonio; Grigoriadis, Nikolaos; Hartung, Hans-Peter; Havrdová, Eva; Hillert, Jan; Hohlfeld, Reinhard; Kremenchutzky, Marcelo; Lyon-Caen, Olivier; Miller, Ariel; Pozzilli, Carlo; Ravnborg, Mads; Saida, Takahiko; Sindic, Christian; Vass, Karl; Clifford, David B; Hauser, Stephen; Major, Eugene O; O'Connor, Paul W; Weiner, Howard L; Clanet, Michel; Gold, Ralf; Hirsch, Hans H; Radü, Ernst-Wilhelm; Sørensen, Per Soelberg; King, John (August 2011). "Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring". Lancet Neurology. 10 (8): 745–58. doi:10.1016/S1474-4422(11)70149-1. hdl:2078.1/124907. PMID   21777829. S2CID   15639613.
  9. ↑ "Dimethyl fumarate (Tecfidera): Fatal PML in an MS patient with severe, prolonged lymphopenia".
  10. ↑ "FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs". US Food and Drug Administration. Retrieved 31 December 2018.
  11. ↑ Radswiki. "Progressive multifocal leukoencephalopathy | Radiology Reference Article | Radiopaedia.org". Radiopaedia. Retrieved 2019-03-09.
  12. 1 2 3 4 Berger JR; Aksamit AJ; Clifford DB; et al. (9 April 2013). "PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section". Neurology. 80 (15): 1430–8. doi:10.1212/WNL.0b013e31828c2fa1. PMC   3662270 . PMID   23568998.
  13. ↑ Wyen, Christoph; Hoffmann, Christian; Schmeier, Norbert; Hoffmann, Andrej; Qurishi, Nazifa; Rockstroh, Jürgen; Esser, Stefan; Rieke, Ansgar; Ross, Birgit; Lorenzen, Thore; Schmitz, Karina; Stenzel, Werner; Salzberger, Bernd; Fätkenheuer, Gerd (2004). "Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death". Journal of Acquired Immune Deficiency Syndromes. 37 (2): 1263–1268. doi: 10.1097/01.qai.0000136093.47316.f3 . PMID   15385733. S2CID   23613081.
  14. ↑ Gray, Françoise; Salmon, Dominique; Thiebault, Jean Baptiste; Gasnault, Jacques; Bienvenu, Boris; Vendrely, Aurélie (2005). "Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy". Acta Neuropathologica. 109 (4): 449–455. doi:10.1007/s00401-005-0983-y. PMID   15739098. S2CID   23865244.
  15. ↑ Vendrely, Aurélie; Bienvenu, Boris; Gasnault, Jacques; Thiebault, Jean Baptiste; Salmon, Dominique; Gray, Françoise (April 2005). "Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy". Acta Neuropathol. 109 (4): 449–55. doi:10.1007/s00401-005-0983-y. PMID   15739098. S2CID   23865244.
  16. ↑ Segarra-Newnham, Marisel; Vodolo, Kristen M (June 2001). "Use of cidofovir in progressive multifocal leukoencephalopathy". Ann Pharmacother. 35 (6): 741–4. doi:10.1345/aph.10338. PMID   11408993. S2CID   32026770.[ permanent dead link ]
  17. ↑ Aksamit, A J (August 2001). "Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside". J. Neurovirol. 7 (4): 386–90. doi:10.1080/13550280152537292. PMID   11517422. S2CID   12159275.
  18. ↑ Langer-Gould, Annette; Atlas, Scott W.; Green, Ari J.; Bollen, Andrew W.; Pelletier, Daniel (July 2005). "Progressive multifocal leukoencephalopathy in a patient treated with natalizumab". N. Engl. J. Med. 353 (4): 375–81. doi: 10.1056/NEJMoa051847 . PMID   15947078.
  19. ↑ Gofton, T. E.; Al-Khotani, A.; O'Farrell, B.; Ang, L. C.; McLachlan, R. S. (June 2010). "Mefloquine in the treatment of progressive multifocal leukoencephalopathy". J Neurol Neurosurg Psychiatry. 82 (4): 452–455. doi:10.1136/jnnp.2009.190652. PMID   20562463. S2CID   19877728.
  20. ↑ Buckanovich RJ1, Liu G, Stricker C; et al. (July 2002). "Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin's lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy". Ann Hematol. 81 (7): 410–3. doi:10.1007/s00277-002-0481-4. PMID   12185517. S2CID   24949477.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  21. ↑ Jamilloux, Y; Kerever, S; Ferry, T; Broussolle, C; Honnorat, J; Sève, P (October 2016). "Treatment of Progressive Multifocal Leukoencephalopathy With Mirtazapine". Clinical Drug Investigation. 36 (10): 783–9. doi:10.1007/s40261-016-0433-8. PMID   27401779. S2CID   34008609.
  22. ↑ Ferenczy, MW; Marshall, LJ; Nelson, CD; Atwood, WJ; Nath, A; Khalili, K; Major, EO (July 2012). "Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain". Clin. Microbiol. Rev. 25 (3): 471–506. doi:10.1128/CMR.05031-11. PMC   3416490 . PMID   22763635.
  23. ↑ Gosert, R; Rinaldo, C.H.; Wernil, M; Major, EO; Hirsch, HH (May 2011). "CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes". Antimicrob. Agents Chemother. 55 (5): 2129–36. doi:10.1128/AAC.00046-11. PMC   3088264 . PMID   21402853.
  24. ↑ Rainer, Gosert; Rinaldo, Christine; Wernli, Marion; Major, Eugene; Hirsch, Hans (2011). "CMX001 (1-O-Hexadecyloxypropyl-Cidofovir) Inhibits Polyomavirus JC Replication in Human Brain Progenitor-Derived Astrocytes". Antimicrobial Agents and Chemotherapy. 55 (5): 2129–2136. doi:10.1128/AAC.00046-11. PMC   3088264 . PMID   21402853.
  25. ↑ Muftuoglu, Muharrem; Olson, Amanda; Marin, David; et al. (2018-10-11). "Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy". New England Journal of Medicine. 379 (15): 1443–1451. doi:10.1056/nejmoa1801540. ISSN   0028-4793. PMC   6283403 . PMID   30304652.
  26. ↑ "Cellevolve Announces Global Partnership with QIMR Berghofer Medical Research Institute to Advance Novel Off-the Shelf T-cell Therapy in the First Randomized Cell Therapy Trial for Progressive Multifocal Leukoencephalopathy (PML)". BUSINESS WIRE. December 2021. Retrieved 3 May 2022.
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