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Reviews

Treatment options for progressive multifocal leukoencephalopathy in HIV-infected persons: current status and future directions

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Pages 177-191 | Received 06 Nov 2015, Accepted 10 Dec 2015, Published online: 04 Jan 2016

References

• First description of PML.

  • Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet. 1971;1:1257–1260.

• First viral cultivation of the virus then named JC virus.

  • Gheuens S, Wüthrich C, Koralnik IJ. Progressive multifocal leukoencephalopathy: why gray and white matter. Annu Rev Pathol Mech Dis. 2013;8:189–215 DOI:10.1146/annurev-pathol-020712-164018.

• Extensive review, clear, and comprehensive.

  • Engsig FN, Hanse AB, Omland LH, et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral era: a nationwide cohort study. Infect Dis. 2009;199:77–83.
  • Khanna N, Elzi L, Mueller NJ, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV cohort study. Clin Infect Dis. 2009;48:1459–1466. DOI:10.1086/598335.
  • Bauer J, Gold R, Adams O, et al. Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome (IRIS). Acta Neuropathol. 2015. DOI:10.1007/s00401-015-1471-7.

• Excellent paper on PML and PML-IRIS.

  • Brew B, Davies N, Cinque P, et al. Progressive multifocal encephalopathy and other forms of JC virus disease. Nat Rev Neurol. 2010;6:667–669. DOI:10.1038/nrneurol.2010.164.
  • Tan K, Roda R, Ostrow I, et al. PML-IRIS in patients with HIV infection. Clinical manifestations and treatment with steroids. Neurology. 2009;72:1458–1464.

• The only report on steroids effects in HIV-related PML-IRIS.

  • Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005;353:375–381.
  • Clifford DB, DeLuca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010;9:438–446.

• This paper evaluated the first 28 cases of natalizumab-associated PML.

  • Tan CS, Koralnik J. Beyond progressive multifocal encephalopathy: expanded pathogenesis of JC virus infection in the central nervous system. Lancet Neurol. 2010;9:425–437. DOI:10.1016/S1474-4422(10)70040-5.

•• Excellent review on pathogenesis of JCV infection.

  • Ferenczy MW, Marshall LJ, Nelson CDS, et al. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus demyelinating disease of the human brain. Clin Microbiol Rev. 2012;25:471–506.

•• Extensive, detailed, still up-to-date review.

  • Pavlovici D, Patera AC, Nyberg F, et al. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord. 2015; 1–19. DOI: 10.1177/1756285602832.

• The most recent review by the PML consortium, following the 2nd conference on PML (August 2015, Sweden).

  • Calabrese LH, Molloy E, Berger J. Sorting out the risks in progressive multifocal leukoencephalopathy. Nat Rev Rheumatol. 2015;11:119–123. DOI:10.1038/nrrheum.2014.167.
  • White MK, Gordon J, Berger JR, et al. Animal models for progressive multifocal leukoencephalopathy. J Cell Physiol. 2015;230:2869–2874. DOI:10.1002/jcp.25047.
  • Tan CS, Broge TA Jr, Seung E, et al. Detection of JC virus-specific immune responses in a novel humanized mouse model. PLoS One. 2013;8:e64313. DOI:10.1371/journal.pone.0064313.
  • Kondo Y, Windrem MS, Zou L, et al. Human glial chimeric mice reveal astrocytic dependence of JC virus infection. J Clin Invet. 2014;124:5323–5336. DOI:10.1172/JCI76629.

• Finally, a more reliable animal model.

  • Hirsch HH, Kardas P, Ranz D, et al. The human JC polyomavirus (JCPyV): virological background and clinical implications. APMS. 2013;121:685–727. DOI:10.1111/apm.12128.

• Another good review.

  • Hernandez B, Dronda F, Moreno S, Treatment options for AIDS patients with progressive multifocal leukoencephalopathy. Expert Opin Pharmacother. 2009;10:40316.

• Important review on PML treatments and effects of antiretrovirals up to 2009.

  • Gorelik L, Reid C, Testa M, et al. Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis. 2011;204:103–114. DOI:10.1093/infdis/jir198.
  • Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic disease. Arthritis Rheum. 2009;60:3761–3765. DOI:10.1002/art.24966.
  • Bellizzi A, Anzivino E, Rodio DM, et al. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Develop Immunol. 2013; Article ID 839719. DOI:10.1155/2013/839719.
  • Van Loy T, Thys K, Ryschkewitsch C, et al. JC virus quasispecies analysis reveals a complex viral population underlying progressive multifocal leukoencephalopathy and supports viral dissemination via the hematogenous route. J Virol. 2015;89:1340–1347. DOI:10.1128/JVI.02565-14.
  • Durali D, De Herve DG, Gasnault J, et al. B cells and progressive multifocal leukoencephalopathy: search for the missing link. Frontiers in Immunology. 2015;6:1–9 article 241. DOI:10.3389/fimmu.2015.00241.
  • Magginis MS, Nelson CDS, Atwood WA. JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection. J Neurovirol. 2014; DOI:10.1007/s13365-014-0272-4.

• Excellent review for understanding JCV infection pathogenesis.

  • Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science. 2004;1380–1383. DOI:10.1126/science.1103492.
  • Pho MT, Ashok A, Atwood WJ. JC virus enters human glial cells by clathrin-dependent receptor-mediated endocytosis. J Virol. 2000;74:2288–2292.
  • Monaco MCG, Major EO. Immune system involvement in the pathogenesis of JC virus induced PML: what is learned from studies of patients with underlying diseases and therapies as risk factors. Front Immunol. 2015;6:1–5. article 159. DOI:10.3389/fimmu.2015.00159.
  • Beltrami S, Gordon J. Immune surveillance and response to JC virus infection and PML. J Neurovirol. 2014;20:137–149. DOI:10.1007/s13365-013-0222-6.
  • Jelcic I, Jelcic I, Faigle W. Immunology of progressive multifocal immunology. Neurovirol. 2015. DOI:10.1007/s13365-0294-y.

• An up-to-date and clear description of PML immunology.

  • Aly L, Yousef S, Schippling S, et al. Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome. Brain. 2011;134:2687–2702. DOI:10.1093/brain/awr206.
  • Khanna N, Wolbers M, Mueller NJ, et al. JCV-specific immune responses in HIV-1 patients with progressive multifocal leukoencephalopathy. J Virol. 2009;83:4404–4411.
  • Berger JR. Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome: explaining the high incidence and disproportionate frequency of the illness relative to other immunosuppressive conditions. J NeuroVirol. 2003;1(suppl.1):38–41. DOI:10.1080/13550280390195261.
  • Fong IW, Toma E. The natural history of progressive multifocal leukoencephalopathy in patients with AIDS. Clin Infect Dis. 1995;20:1305–1310.
  • Berger J, Pall L, Lanska D, et al. Progressive multifocal leukoencephalopathy in patients with HIV infection. J NeuroVirol. 1998;4:59–68.
  • Sudhakar P, Bachman DM, Mark AS, et al. Progressive multifocal leukoencephalopathy and a neuro-ophtalmological review. J Neuro-Ophtalmol. 2015;35:296–305. DOI:10.1097/WNO0000000000000271.
  • Berger JR, Aksmit AJ, Clifford DB, et al. PML diagnostic criteria. Consensus statement from AAN neuroinfectious disease section. Neurology. 2013;80:1430–1438. DOI:10.1212/WNL.0b013e31828c2fa1.

• Proposed criteria for the diagnosis of PML, facilitating the case description for clinical reports and clinical trials.

  • Berger JR. The clinical features of PML. Cleveland Clinic J Med. 2011;78(suppl.2):S8–S12. DOI:10.3949/ccjm.78.s2.03.
  • Fong IW, Britton CB, Luinstra KE, et al. Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Clin Microbiol. 1995;33:484–486.
  • Giacomini PS, Rozenberg A, Metz I, et al. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N Engl J Med. 2014;370:486–488. DOI:10.1056/NEJMc1304828.
  • Schwab N, Schneider-Hohendorf T, Pignolet B, et al. PML risk stratification using anti-JCV antibody index and L-selectin. Mult Sclerosis J. 2015; 1–13. DOI: 10.1177/13524585607651.

• Proposes the use of 2 marquers for PML risk stratification and an algorithm for using them.

  • Schneider-Hohendorf T, Philipp K, Husstedt IW, et al. Specific loss of cellular L-selectin on CD4+ T-cells is associated with progressive multifocal leukoencephalopathy development during HIV infection. AIDS. 2014;28:793–795.
  • Atwood WJ. A combination of low-dose chlorpromazine and neutralizing antibodies inhibits the spread of JC virus (JCV) in a tissue culture model: implications for prophylactic and therapeutic treatment of progressive multifocal leukoencephalopathy. J NeuroVirology. 2001;7:307–310.
  • Nukuzuma S, Nakamichi K, Nukuzuma C, et al. Inhibitory effect of serotonin antagonists on JC virus propagation in a carrier culture of human neuroblastoma cells. Microbial Immunol. 2009;53:496–501. DOI:10.1111/j.1348-0421.2009.00156.x.
  • Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol. 2009;66:255–258.
  • Verma S, Cikurel K, Koralnik I, et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis. 2007;196:709–711. DOI:10.1086/520514.
  • Sano Y, Nakano Y, Omoto M, et al. Rituximab-associated progressive multifocal leukoencephalopathy derived from non-Hodgkin lymphoma: neuropathological findings and results of mefloquine treatment. Intern Med. 2015;54:965–970. DOI:10.2169/internalmedicine.54.2308.
  • Amancha PK, Hong JJ, Rogers K, et al. In vivo blockade of the programmed cell death-1 pathway using soluble recombinant PD-1-Fc enhances CD4+ and CD8+ T cell responses but has limited clinical benefit. J Immunol. 2013;191:6060–6070. DOI:10.4049/jimmunol.1.302044.
  • Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother. 2009;53:1840–1849. DOI:10.1128/AAC.01614-8.
  • Gofton TE, Al-Khotani A, O’Farrell B, et al. Mefloquine in the treatment of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry. 2011;82:452–455. DOI:10.1136/jnnp.2009.190652.
  • Shin J-W, Jung K-H, Lee S-T, et al. Mefloquine improved progressive multifocal leukoencephalopathy in a patient with immunoglobulin A nephropathy. J Neurol Sci. 2014;21:1661–1664. DOI:10.1016/j.jocn.2013.12.031.
  • Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of PML outcomes. J Neurovirol. 2013;19:351–358. DOI:10.1007/s13365-013-0173-y.

• The only clinical trial well designed in spite of difficult challenges to conduct it.

  • Nevin RL. Pharmacokinetic considerations in the repositioning of mefloquine for the treatment of progressive multifocal leukoencephalopathy(letter). Clin Neuro Neurosurg. 2012;114:1204–1205. DOI:10.1016/j.clineuro.2012.02.046.
  • Owen A, Janneh O, Hartkoorn RC, et al. In vitro synergy and enhanced murin brain penetration of saquinavir coadministred with mefloquine. J Pharmac Experim Therap. 2005;314:1202–1209. DOI:10.1124/jpet.105.086272.
  • Dow GS, Hudson T, Vahey M, et al. The acute neurotoxicity of mefloquine may be mediated through a disruption of calcium homeostasis and ER function in vitro. Malaria Journal. 2003; 2:1–14. Available from: http://www.malariajournal.com/content/2/1/14
  • Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS. 2002;16:1791–1797.
  • De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS. 2008;22:1759–1767. DOI:10.1097/QAD.Ob013e32830a5043.
  • Florescu DF, Keck MA. Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses. Expert Rev Anti Infect Ther. 2014;12:1171–1178. DOI:10.1586/14787210.2014.948847.
  • Painter W, Robertson A, Trost LC, et al. First pharmacokinetic and safety in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob Agents Chemother. 2012;56:2726–2734. DOI:10.1128/AAC.05983-11.

• The first pharmacokinetic study of brincidofovir in humans demonstrating its greater bioavailability.

  • Jiang ZG, Cohen J, Marshall LJ, et al. Hexadecycloxypropyl-cidofovir (CMX001) supresses JC virus replication in human fetal brain SVG cell culture. Antimicrob Agents Chemother. 2010;54:4723–4732. DOI:10.1128/AAC.00837-10.
  • Gosert R, Rinaldo CH, Wernli M, et al. CMX001(1-O-hexadecycloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes. Antimicrob Agents Chemother, 2011;55:2129–2136. DOI:10.1128/AAC.00046-11.
  • Papanicolaou GA, Lee YJ, Young JW, et al. Brincidofovir for polyomavirus-associated nephropathy after allogeneic hematopoietic stem cell transplantation. Am J Kidney Dis. 2015;65:780–784. DOI:10.1053/j.ajkd.2014.11.020.
  • Florescu DF, Kalil AC, Hewlett AL, et al. Administration of brincidofovir and convalescent plasma in a patient with Ebola virus disease. Clin Infcet Dis. 2015;61:969–973. DOI:10.1093/cid/civ395.
  • Middel A, Arends JE, Van Lelyveld SFL, et al. Clinical and immunologic effects of maraviroc in progressive multifocal leukoencephalopathy. Neurology. 2015;85:104–106.
  • Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med. 1998;338:1345–1351.
  • Berger JR. Steroids for PML-IRIS. A double-edged sword? Neurology. 2009;72:1454–1455. DOI:10.1212/01.wnl.0000343735.44983.5e.
  • Sierra-Madero JG, Ellenberg SS, Rassool MS, et al. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. Lancet HIV. 2014;2:e60–e67.

•• The only double-blind, randomized trial of maraviroc for the prevention of HIV IRIS.

  • Martin-Blondel G, Cuzin L, Delobel P, et al. Is maraviroc beneficial in paradoxical progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome management? AIDS. 2009;23:2545–2546. DOI:10.1097/QAD.0b013e32833365f4.
  • Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005;353:369–374.
  • Lehmann HC, Krüger K, Fink GR, et al. Progressive multifocal leukoencephalopathy after interferon beta-1a monotherapy. J Neurol. 2015;262:771–773. DOI:10.1007/s00415-014-7620-4.
  • Delbue S, Guerini FR, Mancuso R, et al. JC viremia in interferon-ß-treated and untreated Italian multiple sclerosis patients and healthy controls. NeuroVirol. 2007;12:73–77. DOI:10.1080/13550280601094563.
  • Pellegrini M, Calzascia T, Toe JG, et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell. 2011;144:601–613. DOI:10.1016/j.cell.2011.01.011.
  • Alstadhaug KB, Croughs T, Henriksen S, et al. Treatment of progressive multifocal leukoencephalopathy with interleukin 7. JAMA Neurology. 2014;71:1030–1035. DOI:10.1001/jamaneurol.2014.825.
  • Gasnault J, De Goër De Herve MG, Michot JM, et al. Efficacies of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy. Open Forum Infect Dis. 2014;1:ofu074. DOI:10.1093/ofid/ofu074.eCollection2014Sep.
  • Sospedra M, Schippling S, Yousef S, et al. Treating progressive multifocal leukoencephalopathy with interleukin 7 and vaccination with JC virus capsid protein VP1. Clin Infect Dis. 2014;59:1588–1592. DOI:10.1093/cid/ciu682.

• Giving hopes for future clinical applications.

  • Riddel LA, Pinching AJ, Hill S, et al. A phase III study of recombinant human interferon gamma to prevent opportunistic infections in advanced HIV disease. AIDS Res Human Retorviruses. 2001;17:789–797.
  • De-Simone FI, Sariyer R, Otalora Y-L, et al. IFN-gamma inhibits JC virus replication in glial cells by suppressing T-antigen expression. PLoS One. 2015;10. e0129694. DOI:10.1371/journal.pone.0129694.
  • Balduzzi A, Lucchini G, Hirsh HH, et al. Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. Bone Marrow Transplantation. 2011;46:987–992. DOI:10.1038/bmt.2010.221.
  • Jelcic I, Combaluzier B, Jelcic I, et al. Broadly neutralizing human monoclonal JC polyomavirus VP1-specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy. Sci Transl Med. 2015;7:306ra150. DOI:10.1007/s13365-014-0294-y.

•• Finally, the passive immunotherapy should not be far away.

  • Ray U, Cinque P, Gerevini S, et al. JC polyomavirus mutants escape antibody-mediated neutralization. Sci Transl Med. 2015;7(306):306ra151. DOI:10.1126/scitranslmed.aab1720.

• Describe how to uncover the “blind spots” and prevent JCV immune escape.

  • Hofmeyer KA, Jeon H, Zang X. The PD-1/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T lymphocyte exhaustion. J Biomed Biotechnology. 2011; article ID 451694. 1–9. DOI:10.1155/2011/451694.
  • Velu V, Shetty RD, Larson M, et al. Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options. Retrovirology. 2015;12:14. DOI:10.1186/s12977-015-0144-x.

•• Describe what seems to be a very promising future intervention for chronic infections that could be useful also for PML.

  • Buqué A, Bloy N, Aranda F, et al. Trial watch: immunomodulatory monoclonal antibodies for oncological indications. OncoImmunology. 2015;4(4):e1008814. DOI:10.1080/2162402x.2015.1008814.
  • Yatawara A, Gaidos G, Rupasinghe CN, et al. Small-molecule inhibitors of JC polyomavirus infection. J Pept Sci. 2015;21:236–242. DOI:10.1002/psc.2731.

• An active compound is already synthetized.

  • Zins SR, Nelson CDS, Maginnis MS, et al.. The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffic and stabilizing the viral capsid. J Virol, 2014; 88:948–960. DOI:10.1128/JVI.02766-13.
  • Kennedy EM, Cullen BR. Bacterial CRISPR/Cas DNA endonucleases: a revolutionary technology that could dramatically impact viral research and treatment. Virology. 2015; 478-480:213–220. DOI:10.1016/jj.virol.2015.02.024.

•• Excellent review for understanding this impressive technology.

  • Saayman S, Ali SA, Morris KV, et al. The therapeutic application of CRISPR/Cas9 technologies for HIV. Expert Opin Biol Ther. 2015;15:819–830.
  • Hu W, Kaminski R, Yang F, et al. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Pnas. 2014;111:11461–11466. DOI:10.1073/pnas.1405186111.
  • Zhu W, Lei R, Le Duff Y, et al. The CRISPR/Cas9 system inactivates latent HIV-1 proviral DNA. Retrovirology. 2015;12:22–28. DOI:10.1186/s12977-015-0150-z.
  • Wollebo HS, Bellizzi A, Kaminski R, et al. CRISPR/Cas9 system as an agent for eliminating polyomavirus JC infection. PLoS ONE. 2015;10:e0136046. DOI:10.1371/journal.pone.0136046.

•• The first demonstration of the promising impact of this technology in JCV infection.

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