Skip to main content

Advertisement

SpringerLink
Log in

Immune surveillance and response to JC virus infection and PML

  • Review
  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

The ubiquitous human polyomavirus JC virus (JCV) is the established etiological agent of the debilitating and often fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Most healthy individuals have been infected with JCV and generate an immune response to the virus, yet remain persistently infected at subclinical levels. The onset of PML is rare in the general population, but has become an increasing concern in immunocompromised patients, where reactivation of JCV leads to uncontrolled replication in the CNS. Understanding viral persistence and the normal immune response to JCV provides insight into the circumstances which could lead to viral resurgence. Further, clues on the potential mechanisms of reactivation may be gleaned from the crosstalk among JCV and HIV-1, as well as the impact of monoclonal antibody therapies used for the treatment of autoimmune disorders, including multiple sclerosis, on the development of PML. In this review, we will discuss what is known about viral persistence and the immune response to JCV replication in immunocompromised individuals to elucidate the deficiencies in viral containment that permit viral reactivation and spread.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Achim CL, Wiley CA (1992) Expression of major histocompatibility complex antigens in the brains of patients with progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 51:257–263

    PubMed  CAS  Google Scholar 

  • Aly L, Yousef S, Schippling S, Jelcic I, Breiden P, Matschke J, Schulz R, Bofill-Mas S, Jones L, Demina V, Linnebank M, Ogg G, Girones R, Weber T, Sospedra M, Martin R (2011) Central role of JC virus-specific CD4+ lymphocytes in progressive multi-focal leucoencephalopathy-immune reconstitution inflammatory syndrome. Brain 134:2687–2702

    PubMed  Google Scholar 

  • Andrei G, Snoeck R, Vandeputte M, De Clercq E (1997) Activities of various compounds against murine and primate polyomaviruses. Antimicrob Agents Chemother 3:587–593

    Google Scholar 

  • Antoniol C, Jilek S, Schluep M, Mercier N, Canales M, Le Goff G, Campiche C, Pantaleo G, Du Pasquier RA (2012) Impairment of JCV-specific T-cell response by corticotherapy: effect on PML-IRIS management? Neurology 79(23):2258–2264

    PubMed  CAS  Google Scholar 

  • Astrom KE, Mancall EL, Richardson EP (1958) Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 81:93–111

    PubMed  CAS  Google Scholar 

  • Atwood WJ, Amemiya K, Traub R, Harms J, Major EO (1992) Interaction of the human polyomavirus, JCV, with human B-lymphocytes. Virology 190:716–723

    PubMed  CAS  Google Scholar 

  • Atzeni F, Benucci M, Sallì S, Bongiovanni S, Boccassini L, Sarzi-Puttini P (2013) Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev 12(5):575–579

    PubMed  CAS  Google Scholar 

  • Bayliss J, Karasoulos T, McLean CA (2012) Frequency and large T (LT) sequence of JC polyomavirus DNA in oligodendrocytes, astrocytes and granular cells in non-PML brain. Brain Pathol 22:329–336

    PubMed  CAS  Google Scholar 

  • Berger JR (2010) Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 33(11):969–983

    PubMed  CAS  Google Scholar 

  • Berger JR, Concha M (1995) Progressive multifocal leukoencephalopathy: the evolution of a disease once considered rare. J Neurovirol 1(1):5–18

    PubMed  CAS  Google Scholar 

  • Berger JR, Major EO (1999) Progressive multifocal leukoencephalopathy. Semin Neurol 19(2):193–200

    PubMed  CAS  Google Scholar 

  • Berger JR, Levy RM, Flomenhoft D, Dobbs M (1998) Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 44(3):341–349

    PubMed  CAS  Google Scholar 

  • Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A (2013a) PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology 80(15):1430–1438

    PubMed  PubMed Central  Google Scholar 

  • Berger JR, Houff SA, Gurwell J, Vega N, Miller CS, Danaher RJ (2013b) JC virus antibody status underestimates infection rates. Ann Neurol. doi:10.1002/ana.23893

    PubMed  Google Scholar 

  • Bhattacharyya R, Noch EK, Khalili K (2007) A novel role of Rac1 GTPase in JCV T-antigen-mediated beta-catenin stabilization. Oncogene 26:7628–7636

    PubMed  CAS  Google Scholar 

  • Boldorini R, Cristina S, Vago L, Tosoni A, Guzzetti S, Costanzi G (1993) Ultrastructural studies in the lytic phase of progressive multifocal leukoencephalopathy in AIDS patients. Ultrastruct Pathol 17(6):599–609

    PubMed  CAS  Google Scholar 

  • Brew BJ, Davies NW, Cinque P, Clifford DB, Nath A (2010) Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 6(12):667–679

    PubMed  Google Scholar 

  • Caracciolo V, Reiss K, Khalili K, De Falco G, Giordano A (2006) Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus. Oncogene 25:5294–5301

    PubMed  CAS  Google Scholar 

  • Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN, Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley RL, Sartor O, Green D, Major EO, Bennett CL (2009) Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113(20):4834–4840

    PubMed Central  PubMed  CAS  Google Scholar 

  • Chapagain ML, Nerurkar VR (2010) Human polyomavirus JC (JCV) infection of human B lymphocytes: a possible mechanism for JCV transmigration across the blood–brain barrier. J Infect Dis 202:184–191

    PubMed Central  PubMed  CAS  Google Scholar 

  • Christakis PG, Okin D, Huttner AJ, Baehring JM (2013) Progressive multifocal leukoencephalopathy in an immunocompetent patient. J Neurol Sci 326(1–2):107–110

    PubMed  Google Scholar 

  • Chun TW, Fauci AS (2012) HIV reservoirs: pathogenesis and obstacles to viral eradication and cure. AIDS 26:1261–1268

    PubMed  Google Scholar 

  • Cinque P, Scarpellini P, Vago L, Linde A, Lazzarin A (1997) Diagnosis of central nervous system complications in HIV-infected patients: cerebrospinal fluid analysis by the polymerase chain reaction. AIDS 11(1):1–17

    PubMed  CAS  Google Scholar 

  • Cinque P, Koralnik IJ, Gerevini S, Miro JM, Price RW (2009) Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet Infect Dis 9:625–636

    PubMed Central  PubMed  CAS  Google Scholar 

  • Clifford DB, Yiannoutsos C, Glicksman M, Simpson DM, Singer EJ, Piliero PJ, Marra CM, Francis GS, McArthur JC, Tyler KL, Tselis AC, Hyslop NE (1999) HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 52(3):623–625

    PubMed  CAS  Google Scholar 

  • Clifford DB, Nath A, Cinque P, Brew BJ, Zivadinov R, Gorelik L, Zhao Z, Duda P (2013) A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol 19(4):351-358

    Google Scholar 

  • Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517

    PubMed  CAS  Google Scholar 

  • Daniel DC, Kinoshita Y, Khan MA, Del Valle L, Khalili K, Rappaport J, Johnson EM (2004) Internalization of exogenous human immunodeficiency virus-1 protein, Tat, by KG-1 oligodendroglioma cells followed by stimulation of DNA replication initiated at the JC virus origin. DNA Cell Biol 23:858–867

    PubMed  CAS  Google Scholar 

  • De Luca A, Ammassari A, Pezzotti P, Cinque P, Gasnault J, Berenguer J, Di Giambenedetto S, Cingolani A, Taoufik Y, Miralles P, Marra CM, Antinori A, Gesida 9/99, IRINA, ACTG 363 Study Groups (2008) Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS 22(14):1759–1767

    PubMed  Google Scholar 

  • Del Valle L, Wang JY, Lassak A, Peruzzi F, Croul S, Khalili K, Reiss K (2002) Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors—medulloblastomas. J Neurovirol 8(Suppl 2):138–147

    PubMed  Google Scholar 

  • Del Valle L, Enam S, Lara C, Miklossy J, Khalili K, Gordon J (2004) Primary central nervous system lymphoma expressing the human neurotropic polyomavirus, JC virus, genome. J Virol 78(7):3462–3469

    PubMed Central  PubMed  Google Scholar 

  • Del Valle L, Piña-Oviedo S, Perez-Liz G, Augelli BJ, Azizi SA, Khalili K, Gordon J, Krynska B (2010) Bone marrow-derived mesenchymal stem cells undergo JCV T-antigen mediated transformation and generate tumors with neuroectodermal characteristics. Cancer Biol Ther 9:286–294

    Google Scholar 

  • Delbue S, Elia F, Carloni C, Tavazzi E, Marchioni E, Carluccio S, Signorini L, Novati S, Maserati R, Ferrante P (2012) JC virus load in cerebrospinal fluid and transcriptional control region rearrangements may predict the clinical course of progressive multifocal leukoencephalopathy. J Cell Physiol 227:3511–3517

    PubMed Central  PubMed  CAS  Google Scholar 

  • Dörries K, Arendt G, Eggers C, Roggendorf W, Dörries R (1998) Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy. J Med Virol 54:196–203

    PubMed  Google Scholar 

  • FDA Drug Safety Communication (2012) New risk factor for progressive multifocal leukoencephalopathy (PML) associated with Tysabri (natalizumab). http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm. Accessed 20 Jan 2012

  • Du Pasquier RA, Clark KW, Smith PS, Joseph JT, Mazullo JM, De Girolami U, Letvin NL, Koralnik IJ (2001) JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy. J Neurovirol 7:318–322

    PubMed  Google Scholar 

  • Du Pasquier RA, Kuroda MJ, Schmitz JE, Zheng Y, Martin K, Peyerl FW, Lifton M, Gorgone D, Autissier P, Letvin NL, Koralnik IJ (2003) Low frequency of cytotoxic T lymphocytes against the novel HLA-A*0201-restricted JC virus epitope VP1(p36) in patients with proven or possible progressive multifocal leukoencephalopathy. J Virol 77:11918–11926

    PubMed Central  PubMed  Google Scholar 

  • Du Pasquier RA, Schmitz JE, Jean-Jacques J, Zheng Y, Gordon J, Khalili K, Letvin NL, Koralnik IJ (2004) Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals. J Virol 78:10206–10210

    PubMed Central  PubMed  Google Scholar 

  • Du Pasquier RA, Autissier P, Zheng Y, Jean-Jacques J, Koralnik IJ (2005) Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies. AIDS 19(18):2069–2076

    PubMed  Google Scholar 

  • Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH (2009) Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 199(6):837–846

    PubMed  CAS  Google Scholar 

  • Enam S, Del Valle L, Lara C, Gan DD, Ortiz-Hidalgo C, Palazzo JP, Khalili K (2002) Association of human polyomavirus JCV with colon cancer: evidence for interaction of viral T-antigen and beta-catenin. Cancer Res 62:7093–7101

    PubMed  CAS  Google Scholar 

  • Enam S, Sweet TM, Amini S, Khalili K, Del Valle L. (2004) Evidence for involvement of transforming growth factor beta1 signaling pathway in activation of JC virus in human immunodeficiency virus 1-associated progressive multifocal leukoencephalopathy. Arch Pathol Lab Med 128(3):282–91.

    Google Scholar 

  • Engsig FN, Hansen AB, Omland LH, Kronborg G, Gerstoft J, Laursen AL, Pedersen C, Mogensen CB, Nielsen L, Obel NSO (2009) Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis 199(1):77

    PubMed  Google Scholar 

  • Ferenczy MW, Marshall LJ, Nelson CD, Atwood WJ, Nath A, Khalili K, Major EO (2012) Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 25:471–506

    PubMed Central  PubMed  CAS  Google Scholar 

  • Gallia GL, Safak M, Khalili K (1998) Interaction of the single-stranded DNA-binding protein Puralpha with the human polyomavirus JC virus early protein T-antigen. J Biol Chem 273:32662–32669

    PubMed  CAS  Google Scholar 

  • Gan DD, Khalili K (2004) Interaction between JCV large T-antigen and beta-catenin. Oncogene 23:483–490

    PubMed  CAS  Google Scholar 

  • Gasnault J, Taoufik Y, Goujard C, Kousignian P, Abbed K, Boue F, Dussaix E, Delfraissy JF (1999) Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy. J Neurovirol 5(4):421–429

    PubMed  CAS  Google Scholar 

  • Gasnault J, Kahraman M, Goër de Herve MG, Durali D, Delfraissy JF, Taoufik Y (2003) Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy. AIDS 17:1443–1449

    PubMed  Google Scholar 

  • Gay FW, Drye TJ, Dick GW, Esiri MM (1997) The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 120(Pt 8):1461–1483

    PubMed  Google Scholar 

  • Geschwind MD, Skolasky RI, Royal WS, McArthur JC (2001) The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS. J Neurovirol 7(4):353–357

    PubMed  CAS  Google Scholar 

  • Gheuens S, Pierone G, Peeters P, Koralnik IJ (2010) Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry 81(3):247–254

    PubMed Central  PubMed  Google Scholar 

  • Gheuens S, Wüthrich C, Koralnik IJ (2013) Progressive multifocal leukoencephalopathy: why gray and white matter. Annu Rev Pathol 8:189–215

    PubMed  CAS  Google Scholar 

  • Gorelik L, Reid C, Testa M, Brickelmaier M, Bossolasco S, Pazzi A, Bestetti A, Carmillo P, Wilson E, McAuliffe M, Tonkin C, Carulli JP, Lugovskoy A, Lazzarin A, Sunyaev S, Simon K, Cinque P (2011) Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis 204(1):103–114

    PubMed Central  PubMed  CAS  Google Scholar 

  • Gualco E, Urbanska K, Perez-Liz G, Sweet T, Peruzzi F, Reiss K, Del Valle L (2010) IGF-IR-dependent expression of Survivin is required for T-antigen-mediated protection from apoptosis and proliferation of neural progenitors. Cell Death Differ 17:439–451

    PubMed Central  PubMed  CAS  Google Scholar 

  • Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J (2000) Progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia: a case report and review of reported cases. Clin Infect Dis 31:E20–E22

    PubMed  CAS  Google Scholar 

  • Hall CD, Dafni U, Simpson D, Clifford D, Wetherill PE, Cohen B, McArthur J, Hollander H, Yainnoutsos C, Major E, Millar L, Timpone J (1998) Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med 338(19):1345–1351

    PubMed  CAS  Google Scholar 

  • Helt AM, Galloway DA (2003) Mechanisms by which DNA tumor virus oncoproteins target the Rb family of pocket proteins. Carcinogenesis 24:159–169

    PubMed  CAS  Google Scholar 

  • Houff SA, Berger JR (2008) The bone marrow, B cells, and JC virus. J Neurovirol 14:341–343

    PubMed  Google Scholar 

  • Houff SA, Major EO, Katz DA, Kufta CV, Sever JL, Pittaluga S, Roberts JR, Gitt J, Saini N, Lux W (1988) Involvement of JC virus-infected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy. N Engl J Med 318:301–305

    PubMed  CAS  Google Scholar 

  • Huang SS, Skolasky RL, Dal Pan GJ, Royal W 3rd, McArthur JC (1998) Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study. J Neurovirol 4(3):324–332

    PubMed  CAS  Google Scholar 

  • Jelcic I, Aly L, Binder TM, Bofill-Mas S, Planas R, Demina V, Eiermann TH, Weber T, Girones R, Sospedra M, Martin R (2013) T cell epitope mapping of JC polyoma virus-encoded proteome reveals reduced T cell responses in HLA-DRB1*04:01+ donors. J Virol 87:3393–3408

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kaech SM, Cui W (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12:749–761

    PubMed  CAS  Google Scholar 

  • Kaniowska D, Kaminski R, Amini S, Radhakrishnan S, Rappaport J, Johnson E, Khalili K, Del Valle L, Darbinyan A (2006) Cross-interaction between JC virus agnoprotein and human immunodeficiency virus type 1 (HIV-1) Tat modulates transcription of the HIV-1 long terminal repeat in glial cells. J Virol 80:9288–9299

    PubMed Central  PubMed  CAS  Google Scholar 

  • Kean JM, Rao S, Wang M, Garcea RL (2009) Seroepidemiology of human polyomaviruses. PLoS Pathog 5(3):e1000363

    PubMed Central  PubMed  Google Scholar 

  • Kerr DA, Chang CF, Gordon J, Bjornsti MA, Khalili K (1993) Inhibition of human neurotropic virus (JCV) DNA replication in glial cells by camptothecin. Virology 196(2):612–618

    PubMed  CAS  Google Scholar 

  • Khalili K, Del Valle L, Otte J, Weaver M, Gordon J (2003) Human neurotropic polyomavirus, JCV, and its role in carcinogenesis. Oncogene 22:5181–5191

    PubMed  CAS  Google Scholar 

  • Knowles WA, Pipkin P, Andrews N, Vyse A, Minor P, Brown DW, Miller E (2003) Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 71:115–123

    PubMed  Google Scholar 

  • Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL (1999) JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 52:253–260

    PubMed  CAS  Google Scholar 

  • Koralnik IJ, Du Pasquier RA, Letvin NL (2001) JC virus-specific cytotoxic T lymphocytes in individuals with progressive multifocal leukoencephalopathy. J Virol 75:3483–3487

    PubMed Central  PubMed  CAS  Google Scholar 

  • Koralnik IJ, Du Pasquier RA, Kuroda MJ, Schmitz JE, Dang X, Zheng Y, Lifton M, Letvin NL (2002) Association of prolonged survival in HLA-A2+ progressive multifocal leukoencephalopathy patients with a CTL response specific for a commonly recognized JC virus epitope. J Immunol 168:499–504

    PubMed  CAS  Google Scholar 

  • Krachmarov CP, Chepenik LG, Barr-Vagell S, Khalili K, Johnson EM (1996) Activation of the JC virus Tat-responsive transcriptional control element by association of the Tat protein of human immunodeficiency virus 1 with cellular protein Pur alpha. Proc Natl Acad Sci U S A 93:14112–14117

    PubMed Central  PubMed  CAS  Google Scholar 

  • Krynska B, Gordon J, Otte J, Franks R, Knobler R, DeLuca A, Giordano A, Khalili K (1997) Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein. J Cell Biochem 67:223–230

    PubMed  CAS  Google Scholar 

  • Lashgari MS, Tada H, Amini S, Khalili K (1989) Regulation of JCVL promoter function: transactivation of JCVL promoter by JCV and SV40 early proteins. Virology 170:292–295

    PubMed  CAS  Google Scholar 

  • Levine AJ (2009) The common mechanisms of transformation by the small DNA tumor viruses: the inactivation of tumor suppressor gene products: p53. Virology 384:285–293

    PubMed  CAS  Google Scholar 

  • Li W, Li G, Steiner J, Nath A (2009) Role of Tat protein in HIV neuropathogenesis. Neurotox Res 16(3):205–220

    PubMed  CAS  Google Scholar 

  • Lima MA, Marzocchetti A, Autissier P, Tompkins T, Chen Y, Gordon J, Clifford DB, Gandhi RT, Venna N, Berger JR, Koralnik IJ (2007) Frequency and phenotype of JC virus-specific CD8+ T lymphocytes in the peripheral blood of patients with progressive multifocal leukoencephalopathy. J Virol 81:3361–3368

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lima MA, Bernal-Cano F, Clifford DB, Gandhi RT, Koralnik IJ (2010) Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry 81:1288–1291

    PubMed Central  PubMed  CAS  Google Scholar 

  • Lindå H, von Heijne A, Major EO, Ryschkewitsch C, Berg J, Olsson T, Martin C (2009) Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 361(11):1081–1087

    PubMed  Google Scholar 

  • Major EO (2010) Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med 61:35–47

    PubMed  CAS  Google Scholar 

  • Major EO, Amemiya K, Elder G, Houff SA (1990) Glial cells of the human developing brain and B cells of the immune system share a common DNA binding factor for recognition of the regulatory sequences of the human polyomavirus, JCV. J Neurosci Res 27:461–471

    PubMed  CAS  Google Scholar 

  • Marzocchetti A, Cingolani A, Di Giambenedetto S, Ammassari A, Giancolo ML, Cauda R, Antinori A, De Luca A (2005a) Macrophage chemoattractant protein-1 levels in cerebrospinal fluid correlate with containment of JC virus and prognosis of acquired immunodeficiency syndrome-progressive multifocal leukoencephalopathy. J Neurovirol 11:219–224

    PubMed  CAS  Google Scholar 

  • Marzocchetti A, Di Giambenedetto S, Cingolani A, Ammassari A, Cauda R, De Luca A (2005b) Reduced rate of diagnostic positive detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy. J Clin Microbiol 43(8):4175

    PubMed Central  PubMed  Google Scholar 

  • Marzocchetti A, Lima M, Tompkins T, Kavanagh DG, Gandhi RT, O'Neill DW, Bhardwaj N, Koralnik IJ (2009a) Efficient in vitro expansion of JC virus-specific CD8(+) T-cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy. Virology 383:173–177

    PubMed Central  PubMed  CAS  Google Scholar 

  • Marzocchetti A, Tompkins T, Clifford DB, Gandhi RT, Kesari S, Berger JR, Simpson DM, Prosperi M, De Luca A, Koralnik IJ (2009b) Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 73(19):1551–1558

    PubMed Central  PubMed  CAS  Google Scholar 

  • Mellergard J, Edstrom M, Vrethem M, Emerudh J, Dahle C (2010) Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid. Mult Scler 16:208–217

    PubMed  CAS  Google Scholar 

  • Merabova N, Kaniowska D, Kaminski R, Deshmane SL, White MK, Amini S, Darbinyan A, Khalili K (2008) JC virus agnoprotein inhibits in vitro differentiation of oligodendrocytes and promotes apoptosis. J Virol 82:1558–1569

    PubMed Central  PubMed  CAS  Google Scholar 

  • Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O'Connor PW, Group INMST (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23

    PubMed  CAS  Google Scholar 

  • Miralles P, Berenguer J, García de Viedma D, Padilla B, Cosin J, López-Bernaldo de Quirós JC, Muñoz L, Moreno S, Bouza E (1998) Treatment of AIDS-associated progressive multifocal leukoencephalopathy with highly active antiretroviral therapy. AIDS 12(18):2467–2472

    PubMed  CAS  Google Scholar 

  • Neu U, Maginnis MS, Palma AS, Ströh LJ, Nelson CD, Feizi T, Atwood WJ, Stehle T (2010) Structure-function analysis of the human JC polyomavirus establishes the LSTc pentasaccharide as a functional receptor motif. Cell Host Microbe 8(4):309–319

    PubMed Central  PubMed  CAS  Google Scholar 

  • Niino M, Bodner C, Simard ML, Alatab S, Gano D, Kim HJ, Trigueiro M, Racicot D, Guérette C, Antel JP, Fournier A, Grand'Maison F, Bar-Or A (2006) Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 59:748–754

    PubMed  CAS  Google Scholar 

  • Nukuzuma S, Kameoka M, Sugiura S, Nakamichi K, Nukuzuma C, Takegami T (2013) Suppressive effect of PARP-1 inhibitor on JC virus replication in vitro. J Med Virol 85(1):132–137

    PubMed  CAS  Google Scholar 

  • O'Hara BA, Atwood WJ (2008) Interferon beta1-a and selective anti-5HT(2a) receptor antagonists inhibit infection of human glial cells by JC virus. Virus Res 132(1–2):97–103

    PubMed Central  PubMed  Google Scholar 

  • Padgett BL, Walker DL (1983) Virologic and serologic studies of progressive multifocal leukoencephalopathy. Prog Clin Biol Res 105:107–117

    PubMed  CAS  Google Scholar 

  • Perkins MR, Ryschkewitsch C, Liebner JC, Monaco MC, Himelfarb D, Ireland S, Roque A, Edward HL, Jensen PN, Remington G, Abraham T, Abraham J, Greenberg B, Kaufman C, LaGanke C, Monson NL, Xu X, Frohman E, Major EO, Douek DC (2012) Changes in JC virus-specific T cell responses during natalizumab treatment and in natalizumab-associated progressive multifocal leukoencephalopathy. PLoS Pathog 8:e1003014

    PubMed Central  PubMed  CAS  Google Scholar 

  • Piña-Oviedo S, De León-Bojorge B, Cuesta-Mejías T, White MK, Ortiz-Hidalgo C, Khalili K, Del Valle L (2006) Glioblastoma multiforme with small cell neuronal-like component: association with human neurotropic JC virus. Acta Neuropathol 111(4):388–396

    PubMed  Google Scholar 

  • Puri V, Chaudhry N, Gulati P, Patel N, Tatke M, Sinha S (2010) Progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ T lymphocytopenia. Neurol India 58:118–121

    PubMed  Google Scholar 

  • Raj GV, Khalili K (1995) Transcriptional regulation: lessons from the human neurotropic polyomavirus, JCV. Virology 213(2):283–291

    PubMed  CAS  Google Scholar 

  • Reid CE, Li H, Sur G, Carmillo P, Bushnell S, Tizard R, McAuliffe M, Tonkin C, Simon K, Goelz S, Cinque P, Gorelik L, Carulli JP (2011) Sequencing and analysis of JC virus DNA from natalizumab-treated PML patients. J Infect Dis 204(2):237–244

    PubMed Central  PubMed  CAS  Google Scholar 

  • Royal W 3rd, Dupont B, McGuire D, Chang L, Goodkin K, Ernst T, Post MJ, Fish D, Pailloux G, Poncelet H, Concha M, Apuzzo L, Singer E (2003) Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 9(3):411–419

    PubMed  CAS  Google Scholar 

  • Sariyer IK, Merabova N, Patel PK, Knezevic T, Rosati A, Turco MC, Khalili K (2012) Bag3-induced autophagy is associated with degradation of JCV oncoprotein, T-Ag. PLoS One 7:e45000

    PubMed Central  PubMed  CAS  Google Scholar 

  • Schwab N, Ulzheimer JC, Fox RJ, Schneider-Hohendorf T, Kieseier BC, Monoranu CM, Staugaitis SM, Welch W, Jilek S, Du Pasquier RA, Brück W, Toyka KV, Ransohoff RM, Wiendl H (2012) Fatal PML associated with efalizumab therapy: insights into integrin αLβ2 in JC virus control. Neurology 78(7):458–467

    PubMed Central  PubMed  CAS  Google Scholar 

  • Steinman L (2005) Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 4:510–518

    PubMed  CAS  Google Scholar 

  • Stettner MR, Nance JA, Wright CA, Kinoshita Y, Kim WK, Morgello S, Rappaport J, Khalili K, Gordon J, Johnson EM (2009) SMAD proteins of oligodendroglial cells regulate transcription of JC virus early and late genes coordinately with the Tat protein of human immunodeficiency virus type 1. J Gen Virol 90:2005–2014

    PubMed Central  PubMed  CAS  Google Scholar 

  • Steven NM, Leese AM, Annels NE, Lee SP, Rickinson AB (1996) Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory. J Exp Med 184:1801–1813

    PubMed  CAS  Google Scholar 

  • Stüve O, Dooley NP, Uhm JH, Antel JP, Francis GS, Williams G, Yong VW (1996) Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 40:853–863

    PubMed  Google Scholar 

  • Tada H, Rappaport J, Lashgari M, Amini S, Wong-Staal F, Khalili K (1990) Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells. Proc Natl Acad Sci U S A 87:3479–3483

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tan CS, Dezube BJ, Bhargava P, Autissier P, Wüthrich C, Miller J, Koralnik IJ (2009) Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation. J Infect Dis 199:881–888

    PubMed Central  PubMed  Google Scholar 

  • Tan CS, Bord E, Broge TA, Glotzbecker B, Mills H, Gheuens S, Rosenblatt J, Avigan D, Koralnik IJ (2012) Increased program cell death-1 expression on T lymphocytes of patients with progressive multifocal leukoencephalopathy. J Acquir Immune Defic Syndr 60:244–248

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tan CS, Broge TA, Seung E, Vrbanac V, Viscidi R, Gordon J, Tager AM, Koralnik IJ (2013) Detection of JC virus-specific immune responses in a novel humanized mouse model. PLoS ONE 8(5):e64313. doi:10.1371/journal.pone.0064313

    PubMed Central  PubMed  CAS  Google Scholar 

  • Tassie JM, Gasnault J, Bentata M, Deloumeaux J, Boué F, Billaud E, Costagliola D (1999) Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV. AIDS 13(14):1881–1887

    PubMed  CAS  Google Scholar 

  • Tavazzi E, White MK, Khalili K (2012) Progressive multifocal leukoencephalopathy: clinical and molecular aspects. Rev Med Virol 22:18–32

    PubMed Central  PubMed  Google Scholar 

  • Tretiakova A, Krynska B, Gordon J, Khalili K (1999) Human neurotropic JC virus early protein deregulates glial cell cycle pathway and impairs cell differentiation. J Neurosci Res 55:588–599

    PubMed  CAS  Google Scholar 

  • Tyler KL (2013) PML therapy: “It's Déjà vu all over again”. J Neurovirol, 19(4):311-313

    Google Scholar 

  • Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 353:362–368

    PubMed  Google Scholar 

  • Vermersch P, Kappos L, Gold R, Foley JF, Olsson T, Cadavid D, Bozic C, Richman S (2011) Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 76(20):1697–1704

    PubMed  CAS  Google Scholar 

  • Vugmeyster Y, Kikuchi T, Lowes MA, Chamian F, Kagen M, Gilleaudeau P, Lee E, Howell K, Bodary S, Dummer W, Krueger JG (2004) Efalizumab (anti-CD11a)-induced increase in peripheral blood leukocytes in psoriasis patients is preferentially mediated by altered trafficking of memory CD8+ T cells into lesional skin. Clin Immunol 113(1):38–46

    PubMed  CAS  Google Scholar 

  • Weber F, Goldmann C, Krämer M, Kaup FJ, Pickhardt M, Young P, Petry H, Weber T, Lüke W (2001) Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 49(5):636–642

    PubMed  CAS  Google Scholar 

  • Wei G, Liu CK, Atwood WJ (2000) JC virus binds to primary human glial cells, tonsillar stromal cells, and B-lymphocytes, but not to T lymphocytes. J Neurovirol 6:127–136

    PubMed  CAS  Google Scholar 

  • Winklhofer KF, Albrecht I, Wegner M, Heilbronn R (2000) Human cytomegalovirus immediate-early gene 2 expression leads to JCV replication in nonpermissive cells via transcriptional activation of JCV T antigen. Virology 275(2):323–334

    PubMed  CAS  Google Scholar 

  • Wüthrich C, Koralnik IJ (2012) Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 71:54–65

    PubMed Central  PubMed  Google Scholar 

  • Wüthrich C, Kesari S, Kim WK, Williams K, Gelman R, Elmeric D, De Girolami U, Joseph JT, Hedley-Whyte T, Koralnik IJ (2006) Characterization of lymphocytic infiltrates in progressive multifocal leukoencephalopathy: co-localization of CD8(+) T cells with JCV-infected glial cells. J Neurovirol 12:116–128

    PubMed  Google Scholar 

  • Yoganathan K, Brown D, Yoganathan K (2012) Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a man with AIDS. Int J Gen Med 5:331–334

    PubMed Central  PubMed  CAS  Google Scholar 

  • Yousef S, Planas R, Chakroun K, Hoffmeister-Ullerich S, Binder TM, Eiermann TH, Martin R, Sospedra M (2012) TCR bias and HLA cross-restriction are strategies of human brain-infiltrating JC virus-specific CD4+ T cells during viral infection. J Immunol 189:3618–3630

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This manuscript was sponsored in part by NIH grants awarded to JG and by a Ruth L. Kirchstein National Research Service Award (1T32MH079785) providing support to SB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors SB and JG have declared that no competing interests exist and have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA

    Sarah Beltrami & Jennifer Gordon

  2. Biomedical Neuroscience Graduate Program, Temple University School of Medicine, Philadelphia, PA, USA

    Sarah Beltrami

Authors
  1. Sarah Beltrami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer Gordon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beltrami, S., Gordon, J. Immune surveillance and response to JC virus infection and PML. J. Neurovirol. 20, 137–149 (2014). https://doi.org/10.1007/s13365-013-0222-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-013-0222-6

Keywords

Search

Navigation