Abstract: Interest in pathogenesis of progressive multifocal leukoencephalopathy (PML) followed the observation of the high risk for the disease in HIV infection and the recent observation of an association with a variety of newer therapeutic modalities, e.g., natalizumab, an α4β1 integrin inhibitor, and efalizumab, an anti-CD11a monoclonal antibody. Any hypothesis of PML pathogenesis must account for a number of facts. Firstly, the causative agent JC virus is ubiquitously present, yet only a vanishingly small number of infected persons develop the disease. Secondly, disorders of cell-mediated immunity increase the risk of the disease, particularly HIV infection. Impaired innate immunity is not a risk for PML, and antibodies against JC virus are not protective. Thirdly, a latent period of several months appears necessary following the administration of natalizumab and efalizumab before PML develops. Fourthly, restoration of the immune system can arrest the PML. It is possible that infection with JC virus occurs with a form of the virus shed in the urine of as many as 40% of all adults and present in sewage worldwide. Once acquired, perhaps through an oropharyngeal route, it may replicate and disseminate. A neurotropic form of JC virus that replicates in glial tissues causes PML when immunosurveillance is impaired. There are many unanswered questions with respect to PML pathogenesis. How is virus acquired? What tissues are infected? What is the origin of the neurotropic form? When does virus enter brain? What is the role of central nervous system immunosurveillance? The lack of an animal model has made answering these questions challenging.
Any hypothesis regarding the pathogenesis of progressive multifocal leukoencephalopathy (PML) must reconcile the following facts:
1. The causative virus, a ubiquitous polyoma virus, JC virus, has infected approximately 50% of the world’s population by age 20 and perhaps as many as 70% by late age; yet the disease is vanishingly rare and almost never seen in immunologically healthy individuals.
2. The majority of the immunological abnormalities that predispose to the development of PML are disorders of cell-mediated immunity. The latter may be the consequence of a depletion of lymphocytes or alternatively an alteration of central nervous system (CNS) immunosurveillance.
3. Disorders giving rise to PML frequently affect B cells. Prior to the AIDS pandemic, chronic lymphocytic leukemia (CLL) and other B cell malignancies were the most common underlying predisposing conditions. Others, including AIDS, rheumatological disease, sarcoidosis, tuberculosis, are often associated with B cell activation.
4. Natalizumab, an α4β1 integrin inhibitor, and efalizumab, an anti-CD11a monoclonal antibody, two agents that uniquely predispose to the development of PML require a period of time from their initiation to the occurrence of PML. In the case of natalizumab, the shortest latency has been 8 months and, although the numbers are small with efalizumab, no cases were observed before 4 years of administration. Therefore, how these agents set the stage for PML must require some time to occur.
5. PML was extremely rare prior to the AIDS pandemic. The majority of individuals with PML at that time had an underlying lymphoproliferative disorder. Prior to the availability of highly active antiretroviral agents (HAART), the incidence rate of PML with HIV infection was 7 per 1,000 patient years and as many as 5% of individuals died with the disorder. Following the introduction of HAART, the incidence rate declined to 0.7 per 1,000 (d’Arminio Monforte, 2004). The rate of PML with natalizumab and efalizumab monoclonal antibody therapy averages approximately 1 in 1,000 after 24 to 36 months of treatment.
Unfortunately, there is no animal model of PML. As a consequence, attempts to understand disease pathogenesis are limited to studying the disease in affected humans or in tissue culture. However, several factors have greatly accelerated our understanding of PML pathogenesis. Firstly, the increased incidence of PML due to HIV/AIDS and its appearance with newer biological therapies has provided greater opportunity to study the disease than ever before. Secondly, the development of highly sensitive molecular techniques now allows for the detection of very few copies of a viral genome, particularly, improvements in situ hybridization techniques and ultrasensitive polymerase chain reaction (PCR) (Arthur et al., 1989; Weber et al., 1990). The application of these techniques to tissues available from PML patients has, among other studies, enabled investigations of the mechanisms of viral multiplication, the cellular control over viral gene expression (Amemiya et al., 1989; 1992; Tada et al., 1989), and the delivery of virus to the central nervous system (reviewed in Marshall and Major, 2010; White and Khalili, 2011). Lastly, the recognition of a risk for PML with newer therapies for cancer, solid organ and hematological transplantation, multiple sclerosis, and other diseases has provided an impetus for further research on PML. As with many other microbial disorders (Bowcock, 2010; Newport and Finan, 2011), an interplay of several factors, host factors, the nature of the virus, and the immune response may lay at the heart of pathogenesis.
PML was first described by Astrom, Mancall, and Richardson in 3 patients, 2 with underlying CLL and one with Hodgkin’s disease, in 1958 (Astrom et al., 1958). A review of the literature by the authors found occasional reports dating back to 1930 in which a similar demyelinating disorder was observed in association with a variety of underlying disorders. The etiology of this disorder was unclear and the authors stated, “We do not know the cause of this condition… most frequently a complication of chronic lymphatic leukemia or Hodgkin’s… Whether there is some factor shared in common between these diseases and sarcoidosis and tuberculosis… remains unknown” (Astrom et al., 1958). One year later, Cavanaugh and Greenbaum suggested that a viral etiology based on the electron microscopic appearance of inclusion bodies in the enlarged oligodendroglial nuclei within the PML brain tissue (Cavanaugh et al., 1959). A detailed analysis of the morphology of these inclusion bodies by electron microscopy suggested a papovavirus as the likeliest candidate agent (Silverman and Rubinstein, 1965; ZuRhein, 1965), a class of viruses not previously known to result in central nervous system disorders. This suspicion was confirmed by isolation of the virus in glial cell cultures from the brain of a patient with PML by Padgett and colleagues at the University of Wisconsin (Padgett et al., 1971). Using the initials of the person from whom the virus was initially isolated led to the label JC virus.
JC virus is a non-enveloped, double-stranded DNA virus in the family Polyomaviridae. Previous descriptions of PML occurring in association with other polyomaviruses, e.g., BK virus and SV40 (Weiner et al., 1972), are now believed to have been incorrect. The cases attributed to SV40 have been poorly characterized and, in some instances, re‑examination of these brain tissues by in situ DNA hybridization has revealed JC virus, not SV40 (Stoner and Ryschkewitsch, 1991). BK virus, which shares more than 70% nucleotide homology with JCV (Frisque et al., 1979), is an important cause of renal transplant rejection (Gardner et al., 1971; Tooze, 1980), and can be isolated from the urines of some patients with PML, but has not been proven to be neuropathogenic.
JCV has a simple DNA genome of 5.1 kilobases in a double‑stranded, supercoiled form, encapsidated in an icosahedral protein structure measuring 40 nm in diameter. The DNA codes for six non-structural proteins (large T antigen, small t antigen, T’135, T’136, and T’165, and agnoprotein) (Bollag et al., 2006; Trowbridge and Frisque, 1995) and three capsid proteins (VP1, VP2, VP3) (Figure 1). With the exception of agnoprotein, these regulatory proteins are encoded by 5 transcripts alternatively spliced from the viral early precursor mRNA (Bollag et al., 2006). The large T protein is named for its tumor‑promoting function. In certain rodent and nonhuman primate cells, JCV T protein expression appears to be responsible for malignant transformation or tumor induction, particularly of astroglial cells into astrocytomas (London et al., 1978; Walker et al., 1973; ZuRhein, 1967). The role of JC virus and its protein products in the pathogenesis of human glial and other tumors remains controversial. The large T protein is a non-structural, multifunctional protein that binds DNA and is responsible for initiation of viral DNA replication and transcription of the capsid proteins which are transcribed from opposite strands of the DNA genome.
Between the two coding sequence areas, the early and late genes, are approximately 400 nucleotide base pairs of noncoding sequence referred to as the regulatory or non-coding control region (NCCR). This region of the genome contains the origin of DNA replication as well as elements for promotion and enhancement of transcription and is critical for the cellular tropism of JCV. The JC virus isolated from the kidney is referred to as the archetype sequence and lacks the tandem repeats that are found in the PML brain isolates (Yogo et al., 1990). The form of JC virus found in the PML brain tissue has deletions, substitutions, and duplications in the NCCR compared to the archetype virus (Tominaga et al., 1992; Yogo et al., 1991). The neurotropic forms of JC virus contain an imperfect 98 base pair tandem repeat in the NCCR as typified by the prototypical Mad-1 strain of JC virus. This region of the viral genome demonstrates the most sequence variability in the brains of patients with PML as a consequence of deletions and rearrangements perhaps acquired during propagation in brain or in extraneural host tissues (Dorries, 1984; Martin et al., 1985). Additionally, mutations in the JC virus capsid viral protein 1 (VP1), especially substitutions at positions 55, 60, 267, and 269, appear to increase the risk for the development of PML (Sunyaev et al., 2009). Mutations in VP1 may alter the binding to sialic acid receptors, thus favoring the occurrence of PML (Gorelik et al., 2011).
Initial studies of JC virus derived from PML brain tissue indicated an exclusive neurotropism for glial cells in cultures of human fetal brain cells (Dorries, 1984; Martin et al., 1985; Padgett et al., 1971; ZuRhein, 1965). JC virus infects both oligodendrocytes and astrocytes, but does not routinely infect neurons (Aksamit and Proper, 1988; Wroblewska et al., 1980). However, the observation of CNS disorders attributable to JC virus other than PML renewed interest in the ability of the virus to infect other CNS cells. These disorders include a granular cell degeneration of the cerebellum with cerebellar atrophy first observed in patients with AIDS (Tagliati et al., 1998). Indeed granular cell loss had been previously observed in association with PML. Subsequent studies revealed that JCV could also infect the granular cells of the cerebellum (Koralnik et al., 2005). Another unique disorder due to JC virus is a rarely seen fulminant encephalopathy in immunosuppressed individuals in which the virus infects cortical pyramidal cells (Wuthrich et al., 2009).
JC virus uses a serotonin receptor 5-HT2a linked to sialic acid to bind to the cell surfaces (Elphick et al., 2004). Antibodies directed against this receptor (Elphick et al., 2004) and serotonin antagonists (Nukuzuma et al., 2009) inhibit JC virus propagation in vitro. However, the importance of the serotonin receptor 5-HT2a for infection is not without controversy (Chapagain et al., 2008) and the sialic acid component of the receptor may be most important. JCV uses both alpha(2,3)-linked and alpha(2,6)-linked sialic acids on N-linked glycoproteins to infect cells. The sialic acid linkages required for cell surface binding directly correlate with the linkages required for infection (Dugan et al., 2008). It is not unlikely that other, as yet to be identified, receptors also permit JC virus binding. Following binding, the virus enters the cell through clathrin and eps15 dependent pathways (Pho et al., 2000; Querbes et al., 2004) and is then transported to the endoplasmic reticulum via caveosomes and ultimately to the nucleus (Figure 2). Nuclear DNA binding proteins that selectively interacted with the regulatory region of the genome are critical to the tropism of the virus. Cells that are not permissive to JCV infection probably do not have these same protein factors and/or have other proteins that bind the JCV regulatory sequences and block transcription (Amemiya et al., 1992; Tada et al., 1989).
Acquisition of the Virus
JC virus causes no recognizable clinical illness at the time of initial infection; therefore, the mechanism by which one is infected and the timing of the infection remain unknown. One unequivocal fact is that the virus is ubiquitously found in the human population as indicated by serological studies. The initial serological studies were predicated on the ability of JC virus to hemagglutinate type O erythrocytes (Padgett and Walker, 1983). Subsequently, more highly refined techniques employing immunoassay have been developed and one of these (Gorelik et al., 2010) has recently been licensed commercially. Hemagglutination assay techniques indicate that between the ages of 1 and 5 years, approximately 10% of children demonstrate antibody to JCV, and by age 10, it can be observed in 40-60% of the population (Taguchi et al., 1982; Walker and Padgett, 1983a; 1983b). Using a hemagglutination inhibition assay, Walker and Padgett (1983a) demonstrated that more than 50% of the population were antibody positive by age 20 with small increments of seropositivity noted afterwards. Studies of the prevalence of JCV antibody in otherwise healthy individuals have consistently demonstrated that the highest rates of initial infection occurs prior to the age of 20 with low, but persistent evidence of exposure to the virus in otherwise naïve individuals thereafter (Egli et al., 2009; Gorelik et al., 2010). Studies employing an immunoassay for JC virus have resulted in a broad spread of seroprevalence rates ranging from 35% (Knowles et al., 2003) to 91% (Matos et al., 2010) among adults. Seroconversion rates to JCV have exceeded 90% in some urban areas (Walker and Padgett, 1983a). Although it has been argued that hemagglutination inhibition assays overestimate the frequency of antibody due to cross reactivity with BK virus, there is a fairly high concordance regarding seroprevalence rates across most studies. A recent study employing the commercially licensed test revealed seroprevalence rates in developed countries to range between 48% and 67% in the adult population with multiple sclerosis (Bozic et al., 2011).
The mechanism by which the virus spreads from one person to another is unknown. A respiratory or oropharyngeal transmission has been postulated largely based on the detection of JC virus in tonsillar tissues (Monaco et al., 1998). However, recent studies of these fluids in HIV-infected persons and healthy controls indicate that the virus is rarely demonstrated in them and, when present, is there in very low titer (Berger et al., 2006). On the other hand, JC virus is detected in 98% of sewage samples from diverse geographic regions (Europe, Africa, and North America) and these particles have been found to be stable at 20°C for more than 70 days (Bofill-Mas and Girones, 2001). This observation is perhaps not surprising in light of the high frequency of viral shedding in urine in normal individuals. Between 25% (Rudick et al., 2010) and 40% (Rossi et al., 2007) of non-immunocompromised patients have detectable JC virus in their urine by PCR and, in select populations, that number may be higher (Berger et al., 2006). Therefore, it is probable, though unproven, that the initial infection is via an oral route with the archetype form of JC virus (Bofill-Mas et al., 2003).
The exceeding rarity of PML indicates that the barriers to the development of the disease must be very high. It is likely that these barriers exist in three spheres, the host, the virus, and the immune response. Host factors predisposing to PML remain unexplored; however, parallels may exist with other infectious illnesses. Some examples from other infectious diseases include the role of CCR5-Δ32 polymorphisms in HIV infection (Hutter and Ganepola, 2011), the alteration of Toll-like receptor 3 in aging predisposing to severe neurological disease with West Nile virus (Kong et al., 2008), and the predisposition to herpes simplex encephalitis with inborn errors of interferon alpha/beta and interferon lambda production (Zhang et al., 2008) to name a few. There is a better appreciation of the underlying viral factors and the nature of the immune deficiencies that predispose to the disease.
A number of lines of evidence strongly suggest that PML typically results from reactivation of a latent infection rather than occurs as a consequence of primary infection. Firstly, IgG directed to JC virus structural proteins is almost invariably observed in patients with PML (Knowles et al., 1995; Weber et al., 2001). In one study, only 1 of 21 patients with PML had IgM specific for JCV in their sera, whereas, 20 of 21 had IgG antibody specific for JCV (Padgett and Walker, 1983); however, it is conceivable that these patients were late in the course of their disease. Secondly, although PML has been reported in children (Berger et al., 1992), it is very rare, reflecting the decreased percentage of children who have been exposed to the virus. Thirdly, in at least one patient, plasma and peripheral blood mononuclear cells (PBMCs) obtained 8 months before the onset of PML showed the same genetic makeup of the non-coding control region (Fedele et al., 2003). Fourthly, there have been six individuals with PML from whom lymphoid tissue, spleen, or bone marrow had been obtained 0.5 to 4.1 years before PML and the JCV isolated from these sites have all had the same NCCR genetic profile as that isolated from the brain (Major, personal communications, 2009). Lastly, 43 of 43 patients with natalizumab-associated PML had detectable JC virus antibody in blood samples obtained 16 to 187 months before the diagnosis (Biogen Idec, 2011).
The development of PML is likely a purely stochastic event. For PML to develop, a number of steps must ensue: 1) infection with JC virus; 2) the establishment of latent and/or persistent JC virus infection; 3) rearrangement of JC virus into a neurotropic strain if the initial infection has been with the archetype strain; 4) re-activation of the neurotropic JC virus strain from sites of viral persistence/latency; 5) entry into the brain; 6) establishment of productive infection of oligodendrocytes; and 7) an ineffective immune system that prevents immunosurveillance from eliminating the infection (Table 1). Following the initial infection of JC virus, the virus enters latency in selected tissues. The precise sites of viral latency has not been systematically investigated; however, known sites of viral latency include the tonsils (Monaco et al., 1998), lung, spleen, bone marrow, and kidney (Caldarelli-Stefano et al., 1999). It should also be noted that JC virus DNA, but not JCV protein expression (i.e., latent virus), has been detected by many independent groups in the brains of some individuals who do not have PML, raising the possibility that the virus can enter the brain early in infection and prior to the onset of the symptoms of PML (reviewed by White and Khalili, 2011). Between 25% (Rudick et al., 2010) and 40% (Rossi et al., 2007) of non-immunocompromised patients have detectable JC virus in their urine by PCR and, in select populations, that number may be higher (Berger et al., 2006). These observations suggest that the virus can replicate in, and be shed by, the tubular epithelial cells of the kidney. The DNA sequence of the regulatory region from kidney or urine in these individuals is archetypal and hence is markedly different from the sequence found in the brain of PML patients (Yogo et al., 1991). The neurotropic form of JC virus contains rearrangements not seen in the NCCR of the archetype. Thus either the neurotropic form of the virus is transmitted at low frequency or mechanisms exist within individuals to precisely rearrange the architecture of the JCV virus NCCR.
One view of the pathogenesis of PML has stressed the possible importance of B lymphocytes (Marshall and Major, 2010). Evidence implicates the importance of B lymphocytes in bone marrow or other lymphoid tissues in the life cycle of JCV since regulatory region sequences from JCV DNA in peripheral blood of PML patients are not related to the archetype but are closely related to sequences found in PML brain (Tornatore et al., 1992a). Circulating infected lymphocytes may be able to cross the blood brain barrier and pass infection to astrocytes at the border of vessels, which in turn augments infection through multiplication to eventually infect oligodendrocytes. Using in situ DNA hybridization, JCV‑infected cells are frequently found near blood vessels in the brain, in B lymphocytes in bone marrow and in the brain. In a report of 19 patients with biopsy‑proven PML, over 90% had JCV DNA in peripheral blood lymphocytes using the PCR technology (Tornatore et al., 1992b). Data derived from other groups of individuals without PML revealed that 60% of HIV‑1‑seropositive individuals, 30% of renal transplant recipients, and approximately 5% of normal, healthy volunteers also had JCV DNA in their peripheral circulation (Tornatore et al., 1992b). In relatively immunologically healthy HIV-infected persons on HAART, the likelihood of finding JC virus DNA in circulating lymphocytes appears to parallel that of the normal population (Berger et al., 2005). However, any group whose immune systems suppressed either by immunosuppressive regimens or by diseases, would be considered to be at risk for the development of PML. Other lines of evidence pointing to the importance of the B-cell in the pathogenesis of PML are the high frequency with which the disorder is observed in B-cell malignancies, such as CLL and Hodgkin’s disease, and illnesses associated with B cell activation, such as systemic lupus erythematosus and AIDS. Additionally, the monoclonal antibody natalizumab which appears to carry the highest risk for the development of the disease of any of the biological agents results in hematopoietic stem cell mobilization, particularly, a release of immature cells of B lineage, CD34+ progenitor cells from the bone marrow.
An alternative view of JC virus pathogenesis has emphasized the importance of molecular events in the brain itself in the reactivation of virus from latency and the onset of PML (reviewed by White and Khalili, 2011). Briefly, the detection of neurotropic JC virus DNA, but not viral protein in the brain of some normal individuals without PML, has been reported by many independent laboratories. This implies that the virus can exist in the brain in an inactive or latent state. Since the JC virus NCCR has binding sites for several transcription factors that activate JC virus gene expression and are induced by extracellular cytokines, it is possible that these cytokines are involved in reactivation, e.g., in the cytokine storms evoked in the CNS by HIV/AIDS. There is also evidence that the HIV-1 transactivator Tat is involved in the reactivation of JC virus in glial cells. These data have been reviewed recently (White and Khalili, 2011).
The observation that PML does not develop immediately following the introduction of certain monoclonal antibodies, such as natalizumab and efalizumab, suggests that the evolution of PML with these agents is more than simply the consequence of impaired CNS immunosurveillance; however, the development of PML with other drugs, such as rituximab, seems to occur in a more stochastic fashion, often occurring shortly after their introduction. Unlike the former monoclonal antibodies, this class of drugs predisposing to PML is generally used in conditions that already carry a significant baseline risk for PML. It is quite possible that short intervals from drug administration to PML simply indicates that affected individuals were on the precipice of PML and were tipped over by the drug, perhaps due to impaired CNS immunosurveillance following their introduction. These proposed models of pathogenesis remain conjectural. A schematic of the proposal discussed in this manuscript is found in Figure 2. Clearly, as we learn more from future studies of this virus and the disease, these mechanisms will require refinement.
The authors report no conflicts of interest.
Joseph R. Berger, M.D., Ruth L. Works Professor and Chairman, Department of Neurology, University of Kentucky College of Medicine, 740 S. Limestone St., Lexington, Kentucky 40536, USA.
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