Neuropathology 2015; 35, 487–496


Wor ks hop: N e w p e r s p e ct i v e s i n M S, N M O, a n d P M L

Progressive multifocal leukoencephalopathy: Dot-shaped inclusions and virus-host interactions Yukiko Shishido-Hara1,2 1

Department of Pathology, School of Medicine, Kyorin University and 2Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by reactivation of the asymptomatic persistent pathogen human polyomavirus JC (JC virus). The pathology of affected brain tissues demonstrates oligodendroglia-like cells with viral inclusions in their enlarged nuclei, a diagnostic hallmark of this disease. Today, the pathological features of this disease are expanding, partly due to an unsteady balance between viral virulence and host immunity. Intranuclear viral inclusions were initially thought to be amphophilic materials comprising the entire enlarged nucleus, based on HE staining (full inclusions). Howevewr, recent immunohistochemical analyses detected the presence of intranuclear viral inclusions in dots (dot-shaped inclusions). The dot-shaped inclusions reflect clustered progeny virions at punctuated subnuclear domains called promyelocytic leukemia nuclear bodies, and are indicative of early-stage viral infection or suppressed viral proliferation. Second, the JC virus is usually reactivated in patients with impaired immunity, and therefore the inflammatory reactions are poor. However, the causes of immunosuppression are divergent, as seen with the frequent use of immunosuppressive drugs, including natalizumab. Therefore, the degree of host immunity is variable; some patients show marked anti-viral inflammatory reactions and a good prognosis, indicating that a strong resistance against viral infection remains. Recovery of the immune system may also induce paradoxical clinical worsening, known as immune reconstitution inflammatory syndrome, the mechanism of which has not been clarified. The virus-host interactions have increased in complexity, and the pathology of PML is diverging. In this review, the pathology of PML will be described, with a

Correspondence: Yukiko Shishido-Hara, MD, PhD, Department of Pathology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo 181-8611, Japan. Email: [email protected] Received 16 December 2014; revised and accepted 29 January 2015; published online 6 May 2015.

© 2015 Japanese Society of Neuropathology

focus on the intranuclear target of JC virus infection and host inflammatory reactions. Key words: IRIS, JC virus, natalizumab, PML, progressive multifocal leukoencephalopathy.

INTRODUCTION Progressive multifocal leukoencephalopathy (PML) is a distinct disease entity, first described in 1958 based on its characteristic demyelinating patterns.1 Soon after in 1959, a viral cause was suggested due to the presence of inclusion bodies in the enlarged nuclei of oligodendroglia-like cells.2 In 1965, two independent groups revealed the presence of polyoma-like virions by electron microscopy.3,4 A new human polyomavirus was successfully isolated in 1971 from autopsied brain tissues and cultured with mixed glial cells called primary human fetal glia (PHFG).5 The virus was named the JC virus after the patient. In the 1970s, the JC virus was found to induce brain tumors in experimental animals,6–8 although the oncogenic potential of the JC virus in humans is still controversial. In the early days, PML was a relatively rare disease. The JC virus persists asymptomatically in most populations and is reactivated in those with impaired immunity.Thus, PML was noted to be a “slow viral infection” of the central nervous system, similar to scrapie, Kuru and Creutzfeldt-Jakob disease. In the mid 1980s, the number of PML cases increased dramatically with the acquired immunodeficiency syndrome (AIDS) epidemic. In 1996, highly active antiretroviral therapy (HAART) was initiated in France, and the morbidity and mortality of AIDS decreased.9,10 However, PML remained a major cause of death for AIDS patients, and moreover a new problem, immune reconstitution inflammatory syndrome (IRIS), arose soon after the initiation of HAART. In 2005, the interests of investigators were focused on a new humanized monoclonal antibody, natalizumab, a drug used for multiple sclerosis (MS) and Crohn’s disease. Natalizumab suppresses cellular immunity

488 and significantly increases the risk of JC viral opportunistic infection.11 In Japan, natalizumab became available on June 4, 2014, almost 10 years behind the United States and European countries. Research on PML has progressed in Japan since the isolation of the JC virus Tokyo-1 strain. In 1981, Nagashima et al. reported an autopsy case in which viral isolation was successfully performed using PHFG cells.12,13 The Tokyo-1 strain was the first virus isolated in Japan and one of the three major isolates in the world, together with Mad-1 in the United States and GS/B in Germany.14,15 In 1984, Tokyo-1 was inoculated in golden hamsters, and brain tumor, medulloblastoma was induced.16 In 1987, the regulatory sequence of Tokyo-1 was characterized, and its unique 17-bp insertion in the regulatory region was identified.17 In 2000, the complete 5128-bp sequence of the JC virus Tokyo-1 strain was determined.18 Three capsid proteins, the major capsid protein VP1 and minor capsid proteins VP2 and VP3, are encoded in an overlapping manner downstream of a small regulatory protein called agnoprotein. This viral genome was manipulated molecularly and inserted into a eukaryotic expression vector.19 The first system was established to produce JC virus-like particles (VLPs) in cultured cells.18,19 Using this system, we analyzed the splicing patterns of the JC viral late RNAs and the nuclear transport signals of the capsid proteins. We also identified intranuclear targets of JC viral infection. These findings enabled new pathological observations, “dot-shaped inclusions” in human brain tissues, as described below. Today, PML is recognized more than it was before due to the advancement of basic research and diverging clinical spectra.11,20,21 This review describes the history of PML and

Y Shishido-Hara discusses recent topics, including the intranuclear targets of JC viral infection, promyelocytic leukemia nuclear bodies (PML-NBs),18,22–24 and the JC virus-specific immune response.

CLASSICAL NEUROPATHOLOGY The first cases of progressive multifocal leukoencephalopathy were described in patients with chronic lymphocytic leukemia (CLL) and Hodgkin’s lymphoma in 1958.1 A new disease entity was established, with characteristic distribution patterns of demyelinating lesions in the post mortem brain. A mixture of small and large demyelinating lesions was disseminated around the white-gray matter junctions and in the white matter. Small demyelinating lesions appeared to merge for larger ones (Fig. 1a). Such an arrangement was distinct from those of other demyelinating diseases known in those days, and a new disease entity, progressive multifocal leukoencephalopathy, was established. The demyelinating lesions are most frequently distributed in the cerebral white matter,and the cerebellum, deep grey nuclei, brain stem, and, occasionally, the spinal cord can also be affected. A pathological hallmark of this disease is the presence of oligodendroglia-like cells, which harbor intranuclear inclusions in the enlarged nuclei. These characteristic oligodendroglia-like cells are usually seen at the margins of the demyelinating lesions. Most typically, homogeneous amphophilic materials fill the entire markedly enlarged nucleus (full inclusions) (black arrows in Fig. 1b). However, oligodendroglia-like cells in a variety of nuclear sizes also exist, and some of them seem to lack apparent intranuclear inclusions despite nuclear enlargement (white arrows in

Fig. 1 Neuropathology of the progressive multifocal leukoencephalopathy (PML) brain. (a) Characteristic distribution patterns of demyelinating lesions. In the cerebral hemisphere, small and large lesions are disseminated around the white-gray matter junctions, fusing to each other (KB staining). (b) Histopathology shows enlarged nuclei of oligodendroglia-like cells with amphophilic inclusions (black arrows). In some oligodendroglia-like cells, inclusions are not apparent despite nuclear enlargement (white arrows).

© 2015 Japanese Society of Neuropathology

JC infection and virus-host interactions


Fig. 2 JC viral dot-shaped inclusions. Although JC viral inclusions were initially thought to be amphophilic materials that fill the entire nucleus, according to HE staining (full inclusions), immunohistochemistry demonstrated the presence of intranuclear viral inclusions in dots (dot-shaped inclusions).The dot-shaped inclusions reflect clusters of progeny virions replicated at the punctuated subnuclear domains, promyelocytic leukemia nuclear bodies (PML-NBs), and are indicative of early-stage viral infection (from Y. Shishido-Hara, Acta Neuropathol. 2010; 120: 403–417 with open access).

Fig. 1b). We have found that such enlarged but clear nuclei may contain punctuated JC viral signals frequently seen at the inner nuclear periphery. Immunohistochemistry using anti-JC virus antibodies confirmed the presence of dotshaped inclusions (Fig. 2), which is described in detail below.

NEW NEUROPATHOLOGICAL FINDINGS: DOT-SHAPED INCLUSIONS The JC virus was found to target intranuclear domains called PML-NBs.15,18–20 Because PML happens to also be the abbreviation for “promyelocytic leukemia”, to avoid © 2015 Japanese Society of Neuropathology

confusion in this review, the PML abbreviation is used only to refer to progressive multifocal leukoencephalopathy, while “promyelocytic leukemia” is abbreviated in combination with “nuclear bodies” as PML-NBs. PML-NBs are ubiquitously present in mammalian cells and are associated with a variety of nuclear functions, including DNA repair, transcription, cell cycling, apoptosis, senescence and others.25–29 Many nuclear proteins, including p53, CBP/ p300, Daxx, BLM, Pin1, HDAC7 and pRB, traffic in and out under both normal and pathological cellular conditions, and thus dynamic PML-NBs are structurally and functionally heterogeneous. Pathological associations of PML-NBs have been described in a variety of human diseases,


Y Shishido-Hara

Fig. 3 JC viral genomic organization and its virions. (a) The JC virus Tokyo-1 strain has a 5128-bp double-stranded DNA genome (GenBank accession number: AF030085). The genome is divided into three parts: the regulatory region and the early and late coding regions. In the late coding region, the three capsid proteins VP1, VP2 and VP3 are encoded in an overlapping manner downstream of the agnoprotein. (b) Electron micrograph of JC viral virions, round and filamentous structures, detected in human brain tissue.

including malignant tumors, viral infections and neurological disorders. PML-NBs were initially found to be disrupted in acute promyelocytic leukemia with chromosomal translocation of t(15; 17).30 Disappearance or abolition of PML-NBs was observed in a variety of human cancers of different histological origins.31 Many viruses, including herpes simplex virus-1, cytomegalovirus, Epstein-Barr virus, papillomaviruses and polyomaviruses, target PMLNBs and disrupt their structures.32 In neurological diseases such as spinocerebellar ataxias and Huntington disease, neuronal intranuclear inclusions involving PML-NBs are formed.28 The intranuclear target of JC virus infection was identified with help of a eukaryotic expression system established in 1997.19 Three capsid proteins, VP1, VP2 and VP3, are encoded in an overlapping manner, downstream of a small regulatory protein called agnoprotein, in the late coding region of the viral genome (Fig. 3a).18 Using a eukaryotic expression system, the three capsid proteins were expressed in cells under the regulation of a powerful promoter, and the assembly of VLPs were detected by electron microscopy. They resembled JC virions, round and filamentous structures seen in the oligodendroglial nuclei of human brain tissues (Fig. 3b). This system helped us clarify that the major capsid protein VP1 and the minor capsid proteins VP2 and VP3 are cooperatively transported from the cytoplasm to the nucleus, accumulating in the distinct punctuated subnuclear domains. That is the PML-NBs. Assembly of JC virus-like particles in PML-NBs was first demonstrated in cultured cells by electron microscopy.22 In human brain tissue, PML-NBs are shaped as spherical shells in the enlarged nuclei of oligodendroglia-like

cells. They vary in size but are roughly divided into two types, small PML-NBs (approximately 200–400 nm in diameter) and large PML-NBs (over 1 μm in diameter) (Fig. 4).33,34 Development of intranuclear viral inclusions was analyzed morphometrically.34 Small PML-NBs were frequently seen in the smaller cells (51 1 30.4 μm2), while large PML-NBs were seen in the larger cells (136.7 1 75.8 μm2), indicating that PML-NBs grow in size in association with nuclear enlargement. The viruses produce progenies within the enlarging PML-NBs, and the presence of dot-shaped inclusions is indicative of early-stage infection. Subsequently, the progeny viruses are dispersed throughout the entire part of the nucleus to form full inclusions, and during this process, PML-NBs are disrupted. Development of intranuclear inclusions were found to be associated with the cell cycle transition from the S to G2-like stage, but it is not certain why the virus-infected glial cells undergo cell death, without entering into the M-phase (Fig. 5). Indeed, the JC virus did replicate in cells lacking PML-NBs.35 Thus, it is now hypothesized that PML-NBs are more important for virus-induced cell death than for viral replication itself. The predominant presence of dot-shaped inclusions is indicative of early stage of infection or suppressed viral proliferation, and may be noted with anti-viral inflammatory reactions described below.

PML WITH ANTI-VIRAL INFLAMMATORY REACTIONS MAY INDICATE A GOOD PROGNOSIS The pathology of PML usually presents with poor inflammatory reactions. However, in early 1975, Richardson et al. © 2015 Japanese Society of Neuropathology

JC infection and virus-host interactions

Fig. 4 Promyelocytic leukemia nuclear bodies (PML-NBs) in the enlarged nucleus of oligodendroglia-like cells. PML-NBs vary in size but are divided roughly into two types, small PML-NBs (approximately 200–400 nm in diameter) and large PML-NBs (over 1 μm in diameter). PML-NBs increase in size with cell cycle transition from the S to G2-like state (from Y. Shishido-Hara et al. J Neuropathol Exp Neurol. 2014; 73: 442-53 with permission, open access).

491 had already described atypical cases showing distinct inflammatory reactions and a good prognosis.36 A 54-yearold man receiving immunosuppressive drugs for chronic polymyositis developed PML, the pathology of which showed infiltration of mononuclear inflammatory cells, including numerous plasma cells. However, neurologic manifestations were less devastating than those in typical cases, and the authors concluded that this case possibly represents a strong host resistance against the JC virus. Atypical cases with prolonged survival were also reported by other investigators,37,38 but the prognostic factors were not certain during these early days. In the 2000s, Koralnic and colleagues extensively evaluated the JC virus-specific immune response on the basis of its clinical, pathological and molecular aspects.39–43 The majority of the human population expresses anti-JC virus antibodies, indicating a prior JC viral infection. However, the humoral immune response does not seem to prevent development of demyelinating disease.44 Conversely, the cellular immune responses mediated by CD4+ and CD8+ T lymphocytes were found to play conclusive roles in the suppression of JC viral proliferation.45 The CD8+ cytotoxic T lymphocytes (CTL) are effective players that recognize two human leukocyte antigen A*0201-restricted epitopes of the JC virus major capsid protein VP1.40 Importantly, the patients who survive more than 1 year frequently incur JC virus-specific T cell responses, but rarely do those with a rapid fatal outcome.39,40,46–48 JC virus-specific CTLs were

Fig. 5 Schematic illustration of JC viral inclusion development. Normal oligodendroglial cells have compact small nuclei. After maternal viral infection, the cellular nuclei enlarge, and the cell cycle is activated. Promyelocytic leukemia nuclear bodies (PML-NBs) appear and enlarge in association with cell cycle transition from the S to G2-like state, and progeny virions replicate in PML-NBs to form dot-shaped inclusions. The viruses later disperse throughout the entire nucleus and full inclusions are formed.

© 2015 Japanese Society of Neuropathology


Y Shishido-Hara

Fig. 6 Inflammatory reactions associated with progressive multifocal leukoencephalopathy (PML). The pathology of PML classically shows poor inflammatory reactions, partly due to impaired host immunity. However, some cases show distinct inflammatory reactions with prolonged survival, indicating host resistance to viral infection. Cellular immune responses mediated by CD4+ and CD8+ T cells suppress JC viral proliferation (controlled anti-viral immune response). However, in highly active antiretroviral therapy (HAART)-treated AIDS patients, PML may paradoxically develop with recovery of the immune system (PML-IRIS: immune reconstitution inflammatory syndrome), and some cases show an excess of inflammatory reactions with unbalanced CD4/CD8 ratios and fatal outcomes (uncontrolled immune response).

also detected in healthy individuals, suggesting that these CTLs may play protective roles from PML development.41 However, PML can occur in those with minimal or occult immunosuppression,42 and even in those with normal CD4+ T cell counts and CD4+/CD8+ ratios (immunocompetent individuals).43 Therefore, the mechanisms of JC viral reactivation may not be fully explained by T cell functions alone. Since HAART therapy for AIDS was initiated in 1996, a new clinical issue, IRIS, appeared. HAART therapy improved the host immune system with increased CD4+ T cell counts and decreased HIV viral loads; thus, it was initially expected to protect patients from PML development. However, PML developed in patients after HAART treatment, suggesting new PML onset or worsening of preexisting subclinical PML. This paradoxical PML development, known as PML-IRIS, is usually associated with inflammatory reactions. Although transient worsening of neurological symptoms may be seen, PML in the setting of IRIS may show a favorable outcome. However, in rare cases PML-IRIS can cause severe clinical deterioration, resulting in death.49 The pathology in such fatal cases demonstrates an excessive CD8+ T cell response, often accompanied by macrophages and necrosis. The mechanisms of such uncontrolled CD8+ reactions is not clear, and may be or may not be related with anti-viral inflammatory reactions with balanced CD8+/CD4+ ratios, with a potential alteration between regulated and unregulated immune responses (Fig. 6). Thus, the initiation of HAART induced an increased complexity of the virus-host interaction.

NATALIZUMAB-ASSOCIATED PML Natalizumab (Tysabri, Biogen Idec Inc., Cambridge, Massachusetts, USA), a humanized monoclonal antibody against α4-integrin, is used to reduce cell-mediated immune responses in MS and Crohn’s disease patients. Lymphocytes express α4β1- or α4β7-integrins on their surface, which bind to the vascular cell adhesion molecule-1 (VCAM-1) on endothelial cell surfaces. Following binding, lymphocytes migrate across biological barriers to invade the brain parenchyma.50 Natalizumab prevents lymphocyte adhesion to the endothelial cells. In the United States, natalizumab was introduced to the market in 200451 but was withdrawn due to the risk of PML development on February 28, 2005.52–54 Natalizumab returned to the market in 2006, and became available to MS patients “who have not responded adequately to, or cannot tolerate, other treatments for MS”, with consideration of the benefit-risk balance. The majority of patients receiving natalizumab are from the United States, and many are from European countries. On June 4, 2014, almost 10 years behind these countries, natalizumab became available in Japan. Extensive studies have indicated that the risk of natalizumab-associated PML development depends on three factors: (i) the anti-JC virus antibody serological status; (ii) prior use of immunosuppressants; and (iii) an increased duration of natalizumab treatment.55 The highest estimated risk (incidence, 11.1 cases per 1000 patients) was reported in those positive for anti-JC virus antibodies who had previously used immunosuppressants and had received © 2015 Japanese Society of Neuropathology

JC infection and virus-host interactions natalizumab treatment for 25–48 months.55 The anti-JC virus antibody levels in serum/plasma may be related to the risk of natalizumab-associated PML,56 and a sensitive ELISA has been established to stratify MS patients by higher versus lower risk.57,58 As of September 2, 2014, 492 natalizumab-associated PML cases have been documented among more than 120 000 natalizumab-treated MS patients, with an overall survival rate of 78% (Biogen Idec, data on file). In contrast to the high mortality PML rate among AIDS patients, the natalizumab-associated PML mortality rate was 22%, as of September 2, 2014. Early PML detection is required with conscientious monitoring using MRI, hopefully before the appearance of neurological manifestation (asymptomatic PML).59–61 Once PML develops, reconstitution of the host immune system is required after discontinuation of the drug. Plasmapheresis/immunoadsorption (PLEX/IA) may be managed to accelerate natalizumab clearance. However, similar to HAAT-treated AIDS patients, IRIS can occur in natalizumab-treated MS patients after cessation of the drug.62 Nearly all natalizumabassociated PML patients develop IRIS or show IRIS-like inflammatory reactions.63 Therefore, a brain biopsy should be performed to differentiate among: (i) ongoing PML with or without inflammatory host resistance; (ii) natalizumabassociated PML with fatal IRIS; and (iii) MS exacerbation. Diagnostic differentiation is important for clinicians to determine whether to stop medication (steroids, immunosuppressive therapy) for active PML or to further suppress inflammation using steroids for fatal PML-IRIS;64 however, evaluation of the inflammatory reactions can be difficult in some cases. Severe inflammatory reactions with predominant CD8+ T cells may be seen with fatal PML-IRIS that develops in natalizumab-withdrawn MS patients.64 Excessive CD8+ T cell reactions may be seen in both demyelinating lesions and non-demyelinating adjacent gray and white matter,64–66 resembling HAART-treated AIDS cases. However, interestingly, in natalizumab-withdrawn MS patients, fatal PML-IRIS may also occur together with predominant CD4+ T cell reactions.67 Thus, the nature of fatal PML-IRIS would constitute an uncontrolled immune response with an unbalanced CD4+/CD8+ T cell ratio, but its mechanism is not yet fully understood (Fig. 7).

CONCLUSION Today, PML has attracted attention due to its diverging pathology. PML-NBs were identified as an intranuclear target of JC virus infection, and the presence of dot-shaped inclusions was detected. Frequent use of immunosuppressive drugs also revealed the complicated virus-host interactions, which caused a divergent spectrum of PML. © 2015 Japanese Society of Neuropathology


Fig. 7 The balance of the virus-host interaction is a prognostic factor of progressive multifocal leukoencephalopathy (PML). (a) The JC virus asymptomatically infects most of the human population. In healthy individuals, the immunity of the host suppresses proliferation of the virus. (b) In immunosuppressed patients, the JC virus proliferates and causes PML. Inflammatory reactions are usually poor (classical PML). (c) In rare cases, distinct inflammatory reactions may be seen, indicating strong host resistance and a good prognosis (PML with controlled anti-viral inflammation). (d) However, inflammatory reactions are not always favorable. Excess inflammatory reactions may occur with recovery of the immune system in highly active antiretroviral therapy (HAART)treated AIDS patients or in natalizumab-withdrawn MS patients. The mechanisms of fatal PML-IRIS (immune reconstitution inflammatory syndrome) are still unclear for the most part.


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Further studies are required to better understand the virushost interactions and appropriately diagnose inflammatory reactions associated with PML.

ACKNOWLEDGMENTS I thank Drs. Hiroshi Kamma (Department of Pathology, Kyorin University School of Medicine) and Toshiki Uchihara (Laboratory of Structural Neuropathology, Tokyo Metropolitan Institute of Medical Science) for their continuous support of this research. This work is supported, in part, by the Research Committee of Prion Disease and Slow Virus Infection and by the Research Committee of Molecular Pathogenesis and Therapies for Prion Disease and Slow Virus Infection, The Ministry of Health, Labour and Welfare, Japan.

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Progressive multifocal leukoencephalopathy: Dot-shaped inclusions and virus-host interactions.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by reactivation of the asymptomatic persistent pathogen human...
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