Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Historical Association of Immunological Risk Factors and JCV with PML

Before the AIDS pandemic and the use of immunomodulatory therapy, progressive multifocal leukoencephalopathy (PML) was an extremely rare disease, associated primarily with underlying neoplastic conditions causing a defect in immune function (20, 419). Interestingly, PML was associated mainly with B cell lymphoproliferative disorders (57, 198), which have been hypothesized to lead to the spread of virus from potential sites of latency to the brain. Accounts of potential cases of PML can be traced back as far as 1930 (29, 85, 181, 419, 537). The first case of demyelinating disease described with the term PML was found in a patient with chronic lymphocytic leukemia (CLL) and Hodgkin's lymphoma in 1958 (20). These cases are all consistent with the pathology of PML, including the development of multiple white matter plaques in the brain stem, basal ganglia and thalamus, cerebral hemispheres, and cerebellum.

A viral cause of PML was proposed in 1959 due to observations of inclusion bodies in the nuclei of damaged oligodendrocytes (70) and the hypothesis that the distribution of lesions could be explained by an atypical viral infection (419). The nuclei of cells with inclusion bodies were found by electron microscopy to contain particles similar to known polyomaviruses (202, 559, 560). The etiological agent of PML was not isolated until 1971, when the virus was isolated from a mixed culture of glial cells following a “blind” passage (380) and named JC virus (JCV), after the initials of the patient. More recently, JCV has been termed JC polyomavirus (JCPyV), but this review will maintain the more common nomenclature of “JCV.”

JCV was found to be a nonenveloped icosahedron of 40 nm diameter, which, unlike simian virus 40 (SV40), could cause hemagglutination (HA) of human type 0 erythrocytes (377), which provided means to perform seroepidemiological studies. Data from these studies indicated that JCV was found globally (58), that seroconversion of a large percentage of the population occurred before adulthood (431, 522), and that healthy people, including pregnant women, produced immunoglobulin G (IgG) against JCV (17, 99). Therefore, PML was likely to be caused by reactivation of a latent infection (57, 379, 522). For a full review of the historical association of JCV and PML, see reference 301 and references therein.

PML ceased to be a rare disease after HIV became widespread in the human population. Estimates of the occurrence of PML in AIDS patients range from 3 to 5% (299). The incidence of PML in AIDS patients is significantly greater than that in persons with other underlying causes of immunosuppression (299). Notably, PML incidence has decreased less significantly than other opportunistic infections since the advent of highly active antiretroviral therapy (HAART) (103, 546). It is unclear why PML occurs more frequently in AIDS patients than in those with other underlying causes of immunosuppression, although some causes may include changes in immune cell trafficking, blood-brain barrier (BBB) permeability and cytokine secretion, interaction between viral proteins in coinfected cells, and damage to the brain caused by neuronal HIV infection. HIV likely affects both the immune system and the local cellular environment in ways that increase the risk of progression to PML.

The development of PML as a side effect of immunomodulatory therapy is a growing concern, with reports of fatal PML cases in patients treated with natalizumab (Tysabri) for multiple sclerosis (MS) and Crohn's disease, with rituximab (Rituxan) for multiple sclerosis, non-Hodgkin's lymphoma, rheumatoid arthritis, autoimmune hematological disorders, myasthenia gravis, systemic lupus erythematosus (SLE), and B cell lymphoma, with efalizumab (Raptiva) for plaque psoriasis, with infliximab (Remicade) for psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis, and with mycophenolate mofetil (Cellcept) for suppression of organ transplant rejection (315). These therapies target immune cells, inhibiting their biological function. The risk of PML during natalizumab treatment rises as treatment progresses. The true overall incidence of PML due to natalizumab therapy is currently estimated at 3.85 per 1,000 patients (available for prescribing physicians at https://medinfo.biogenidec.com) and approximately 1 per 500 efalizumab patients. Prescription labeling for mycophenolate mofetil contains a warning of PML risk. Natalizumab and rituximab contain FDA-mandated “black box warnings” because of the risk of PML (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/), while efalizumab has been voluntarily withdrawn from the market because of concerns about the frequency of occurrence of PML (299). Although these therapies are effective for their intended use, the incidence of PML, a deadly disease with no approved treatment, limits their use. Thus, continued research and a more thorough understanding of JCV biology, epidemiology, and pathology are of continued and increasing importance.

Viral Structure, Proteins, and Genome

JCV, like all polyomaviruses, is a nonenveloped, T = 7 icosahedral virus with a closed circular, supercoiled, double-stranded DNA genome. The capsid is composed of three viral structural proteins, VP1, VP2, and VP3, with VP1 being the major constituent. There are 72 pentamers, each composed of five VP1 molecules and one molecule of either VP2 or VP3 (302). Only VP1 is exposed on the surface of the capsid, and it thus determines receptor specificity. Polyomavirus DNA is nucleosomal in structure, with approximately 25 nucleosomes composed of viral DNA and host cell histones contained in each minichromosome, as determined for SV40 (12, 264, 333). The viral particle does not contain linker histones, but the genome acquires them after entry into the host cell.

The prototype JCV genome (Fig. 1) is 5,130 bp (154), although individual variants differ in length, due to alterations in their noncoding regions (see Fig. 3). The genome encodes 6 major viral proteins (large T and small t antigens, VP1, VP2, VP3, and agnoprotein) as well as several splice variants of T antigen. Early- and late-transcribing sides of the genome are physically separated by a noncoding control region (NCCR), often called the hypervariable regulatory region (HVRR) or regulatory region (RR), and are transcribed in opposite directions from opposite strands of DNA. The early side of the genome, which is transcribed before DNA replication begins, is composed of large T antigen and small t antigen genes, as well as the splice variants T′₁₃₅, T′₁₃₆, and T′₁₆₅. The late side of the genome is transcribed concomitant with DNA replication and encodes the three viral structural proteins, VP1, VP2, and VP3, as well as the accessory agnoprotein.

Large T antigen and its variants are multifunctional, interacting with both host and viral proteins as well as with both host and viral DNAs. The T proteins are involved in driving the host cell toward S phase for viral replication, regulating transcription from the host and viral genomes, and directly participating in viral DNA replication. The agnoprotein is less well studied but also appears to be multifunctional, and highly varied functions have been attributed to it (reviewed in reference 238), ranging from viral transcriptional regulation to inhibition of host DNA repair to functioning as a viroporin (478).

Virus Receptors

In all polyomaviruses studied to date, initial binding to host cells involves an interaction with negatively charged sialic acid-containing receptors. The early binding and entry events in the related polyomaviruses SV40 and murine polyomavirus (mPyV) have been extensively studied and contribute to our understanding of JCV pathogenicity. The monosialylated ganglioside GM1 is the major receptor for SV40 (26, 63, 499). SV40 has also been shown to use the class I major histocompatibility complex protein 1 as a receptor in some cases (54, 366, 468). Initially, it was thought that SV40 was not able to attach to sialic acids, as neuraminidase treatment of host cells did not reduce infectivity, although it was later shown that neuraminidase fails to cleave sialic acid off GM1 (88, 337). This interaction between SV40 and GM1 is extremely specific, as SV40 preferentially binds to N-glycolyl GM1 over N-acetyl GM1, which differ by a single hydroxyl group (63). Additionally, although a single VP1 molecule binds GM1 weakly, the multivalent viral capsid is expected to bind GM1 molecules on the plasma membrane with an affinity that is several orders of magnitude greater (362).

Early studies with mPyV demonstrated that the virus binds to α2,3- and α2,6-linked sialic acids on host cells (61, 62, 149, 383). Subsequently, the mPyV was shown to bind to sialic acids present on the ganglioside receptors GD1a and GT1b (461, 499). Although mPyV utilizes gangliosides for productive infection, the virus will bind to sialic acids present on glycoproteins (397). Binding of mPyV to cell surface glycoproteins targeted the virus to a nonproductive pathway for degradation, suggesting that these glycoproteins represent nonproductive pseudoreceptors. The specific interactions between mPyV and sialic acids also play a critical role in pathogenicity. Early studies demonstrated that while both small- and large-plaque variants of mPyV were able to bind to α2,3-linked sialic acids, small-plaque variants were additionally able to bind α2,6-linked sialic acids due to a single point mutation in VP1 (62, 148, 469, 470). As a result, large-plaque variants bound to cells less tightly. This reduced binding also increased pathogenesis of mPyV in mice, indicating that the reduced binding to sialic acids increased viral spread (123, 148).

JCV also requires sialic acid to infect cells and has been reported to utilize both α2,3- and α2,6-linked sialic acids to infect permissive glial cells (125, 284). After stripping glial cells of α2,3- and α2,6-linked sialic acids, each linkage was reconstituted using linkage-specific sialyltransferases. Restoring either α2,3- or α2,6-linked sialic acids to cells rescued infection, indicating that both α2,3- and α2,6-linked sialic acids play an important role in infection (125). The sialyltransferases used were also specific for adding carbohydrate to N-linked glycoproteins, and as infection was fully restored, it was suggested that an N-linked glycoprotein containing either α2,3- or α2,6-linked sialic acid was sufficient for virus infection.

Recently, a receptor moiety used by JCV for productive infection has been identified. Using glycan arrays, a recombinant JCV VP1 pentamer has been shown to bind specifically to lactoseries tetrasaccharide C (LSTc), which contains a terminal α2,6-linked sialic acid (361). This unusual molecule adopts an “L” shape, and JCV specifically binds this molecule by interacting with not only the terminal α2,6-linked sialic acid but also the adjacent GlcNAc sugar. Comparing the crystal structures of SV40 in complex with a portion of GM1 and of JCV in complex with LSTc reveals that the α2,3 versus α2,6 linkages and the favorable interactions between JCV and GlcNAc largely determine binding specificity. Sialylparagloboside, which is identical to LSTc except for its terminal α2,3-linked sialic acid, does not bind JCV. Although α2,3-linked sialic acids were present on the glycan array, none demonstrated appreciable binding to the VP1 pentamer. When the multivalent JCV virus-like particles (VLPs) were used, low binding to some α2,3-sialic acids, including the gangliosides GM2 and GM1, was seen. Therefore, it appears likely that JCV primarily uses α2,6-linked sialic acids to bind to cells, with the possibility that the weak interactions between JCV and α2,3-linked sialic acids play a limited role in infection. It is currently unknown onto what receptor molecule the LSTc moiety is attached.

Viral DNA recovered from cerebrospinal fluid specimens (CSF) from patients with PML has been shown to code for amino acid substitutions of several VP1 residues responsible for binding to sialic acids (477). These mutations are predicted to reduce binding to sialic acids, although it is unclear whether these mutations will confer a selective advantage in patients, as similar mutations clearly reduce infectivity of JCV in tissue culture (362). Alternatively, these mutations may result in a selective advantage similar to that seen in mPyV by preventing nonproductive adsorption to cells that are not permissive for JCV infection. However, these mutations appear to block binding to both α2,3- and α2,6-linked sialic acids, and JCV VLPs containing these mutations show a reduced hemagglutination ability and a decreased ability to bind gangliosides (172, 361). Interestingly, these mutations were recovered only in the CSF and bloodstream and not in the same patient's urine. As only a single genotype of virus was recovered in each patient, it appears that these mutations arose from positive selection of a single JCV population (413). It is currently unclear whether these mutations arise in the CNS of PML patients or originate in peripheral sites before trafficking to the brain. Further studies will be necessary to determine the effects of these mutations on JCV pathogenesis.

In addition to using sialic acid as a receptor, JCV has been shown to require the serotonin receptor, 5HT_2AR, to infect glial cells (130). The initial observations were centered around the fact that antipsychotic drugs such as chlorpromazine (Thorazine) and clozapine potently inhibit virus infection (30). As these drugs antagonize both serotonin and dopamine receptors, it was hypothesized that one or both of these neurotransmitter receptors might function as a virus receptor on glial cells. Subsequent studies using drugs that specifically antagonized dopamine or serotonin receptors suggested that the 5HT_2A subtype of the serotonin receptor functioned as a JCV receptor (130, 373). It was then shown that expression of the 5HT_2A receptor was sufficient to allow viral entry to cells lacking this receptor (HeLa and HEK293A) and that antibodies to the 5HT_2AR blocked infection (130, 296). These data when taken together strongly support a role for 5HT_2AR in JCV infection of glial cells. In vivo data demonstrate increased expression of the 5HT_2A receptor in and around PML lesions, further supporting a critical role for this receptor in the pathogenesis of PML (unpublished observations). Interestingly, infection of 5HT_2AR-expressing cells remains neuraminidase sensitive, confirming a prominent role for cellular carbohydrates in infection (unpublished observations). The 5HT_2AR protein contains several potential glycosylation sites, but it is unclear whether LSTc or other sialic acid moieties responsible for infection reside on this protein. Elimination of glycosylation sites on 5HT_2AR also prevents receptor expression of the cell surface, preventing a clear consensus on the need for sialic acids on 5HT_2A for infection (296). Alternatively, LSTc may instead be present on other sialic acid-containing molecules. One group has found that JCV can infect human brain microvascular endothelial cells that lack the 5HT_2A receptor (75). Infection in their system was very inefficient, but the results indicate that virus infection can proceed by alternative mechanisms on some cell types. Additionally, gangliosides may play a role in JCV infection, and the ganglioside GT1b has been reported to function as a receptor for JCV (248).

Virus Entry

Unlike mPyV, SV40, or BK virus (BKV), JCV enters cells by clathrin-dependent endocytosis (389; reviewed in reference 500) (Fig. 2). Pharmacological inhibitors and expression of dominant negative proteins directed at clathrin-dependent endocytosis inhibit virus infection, whereas inhibition of caveola-dependent endocytosis has no effect on replication (389). Consistent with clathrin-mediated endocytosis, JCV traffics from clathrin-coated pits to Rab5-positive early endosomes, a step that is blocked by dominant negative Eps15 mutants (398) (Fig. 2). Additionally, JCV colocalizes with green fluorescent protein (GFP)-labeled Rab5, and expression of dominant negative inhibitors to Rab5 prevent infection. Subsequently, JCV colocalizes with cholera toxin B, a marker for lipid-mediated endocytosis used by SV40 and mPyV, in compartments that are most likely caveolin-1-positive late endosomes (traditionally referred to as caveosomes) (134, 140, 399). Surprisingly, JCV does not colocalize with markers for Rab7 late endosomes, and expression of the dominant negative form of Rab7 does not inhibit infection. This suggests that trafficking to Rab7-positive late endosomes is not necessary for infection and that virions may leave the normal endocytic pathway from Rab5-positive endosomes or Rab5- and Rab7-positive maturing endosomes. At 12 to 16 h postinfection, JCV colocalizes with the endoplasmic reticulum (ER) protein calregulin, suggesting that JCV traffics to the ER for productive infection. Treatment of cells with brefeldin A, which inhibits COP1-mediated ER trafficking, potently inhibits infection, which further suggests that trafficking of JCV to the ER is a critical step in infection (399).

There is probably much to be learned from SV40 and mPyV that has not been determined for JCV. Delivery of polyomaviruses to the ER is a critical step in infection. In the ER, both mPyV and SV40 interact with components of the host protein folding and quality control machinery for productive infection. It has been demonstrated that mPyV interacts with the protein disulfide isomerase (PDI) family of proteins PDI, ERP57, ERP72, and ERP29 (297, 521). The 72 VP1 pentamers that associate to form the viral capsid are stabilized by interactions between the C-terminal residues of neighboring pentamers, disulfide bonds formed between neighboring pentamers, and calcium ions coordinated by the viral capsid (276). Interaction with the PDI family of proteins, which can isomerize and disrupt disulfide bonds, is able to disrupt interpentameric binding and capsid stability. ERp29 contains only a single catalytic site yet retains its isomerization ability (187). ERp29 interacts with mPyV, and this interaction results in exposure of the C-terminal domain of VP1 (297, 401). Additionally, the previously internalized minor capsid proteins, VP2 and VP3, are exposed as a result of interaction with ERp29. This results in an altered virion that is capable of binding and penetrating lipid bilayers (297, 400). Since the exposure of the C-terminal domain of VP1 requires disulfide bond disruption, additional PDI proteins appear to be necessary for infection by mPyV. Recently, PDI and ERp57 have been identified as acting in a cooperative fashion with ERp29 to reduce and isomerize the mPyV interpentameric disulfide bonds (521).

In related work, similar ER-associated factors were found to play critical roles in SV40 disassembly (443). Inhibition of endogenous cellular PDI and ERp57 by small interfering RNA (siRNA) reduced SV40 infectivity. Unlike the case for mPyV, knockdown of ERp29 had no effect on SV40 infection. Additionally, in vitro interaction between ERp57 and SV40 uncoupled the 12 five-coordinated VP1 pentamers of SV40. It is likely that in the high-calcium environment of the ER, these pentamers remained attached to the virion. However, upon exit from the ER, the low-calcium environment of the cytosol allows for release of these pentamers.

A second critical step in the ER is the translocation of the virion across the ER membrane. As a result of recent studies, it appears likely that polyomaviruses utilize the ER-associated degradation (ERAD) pathway to traffic through a retrotranslocation pore and gain entry to the cytoplasm. Using short hairpin RNAs (shRNAs), Derlin-2 was identified as playing a critical role in mPyV infection. Derlin-2 is a protein involved in the transport of misfolded proteins out of the ER and into the cytoplasm to be degraded (277). Subsequently, Derlin-1 and SelL1, two proteins involved in the ERAD pathway, were found to be important in SV40 infection (443). These interactions are predicted to facilitate the release of a partially disassembled and destabilized virion into the cytosol. For SV40, it has recently been demonstrated that intact virions penetrate the ER membrane during retrotranslocation to the cytosol (210). This suggests that either the retrotranslocation pore used by SV40 is large enough to accommodate a 40-nm virion or the hydrophobic capsid residues exposed in the ER facilitate perforation of the ER membrane and allow an intact virion to enter the cytosol.

After retrotranslocation, the low calcium concentrations encountered by the virus in the cytosol further disrupt capsid stability. This destabilization is believed to result in shedding of a number of the previously attached viral pentamers (443). As a result, nuclear localization signals are exposed, resulting in transport of this partially disassembled virion to the nucleus through the nuclear pore (212, 226, 354, 548). It is likely that some combination of VP1, VP2, and VP3 remains associated with the viral genome during nuclear entry, as minichromosomes that contain the viral genome and nucleosomes do not efficiently enter the nucleus when microinjected into cells (354).

Thus, it is becoming increasingly clear that polyomaviruses utilize a complicated and novel pathway among viruses to ultimately gain access to the host cell nucleus. JCV binds sialic acids similarly to other polyomaviruses yet enters cells by clathrin-mediated endocytosis, suggesting that gangliosides may not play a role in JCV entry. Further experiments will be necessary to determine which receptor molecules contain the sialic acids to which JCV binds for productive infection. It will also be important to determine the similarities between JCV, mPyV, and SV40 in the later steps of virus entry and trafficking.

Cell Type Specificity of JCV

Unlike other polyomaviruses such as BKV and SV40, JCV shows a more restricted host cell range, which has made biochemical and molecular studies difficult. The viral T antigen interacts specifically with human DNA polymerase, restricting the host range in which JCV can replicate (142). Originally, JCV isolates were able to be grown only in human brain cells (540, 541). In order to facilitate biochemical studies of the virus, several other culture models were developed. SVG cells are T antigen-dependent, immortalized human fetal brain cells derived by transducing a heterogeneous culture of human fetal brain cells with a nonreplicating, origin-defective SV40 vector that expresses the SV40 T antigen (303). These cells allowed for the growth of JCV stocks and the study of viral gene expression and replication. Later, it was demonstrated that human fetal astrocytes in culture could support JCV replication, raising the possibility that JCV could replicate in cells other than oligodendrocytes (307).

Several other cell lines that support JCV replication have been established. A JCV-induced owl monkey glioblastoma cell line which spontaneously produced the Mad-4 variant of JCV was established in tissue culture (308). Transformed Rat2 cells were established to study JCV-induced transformation in culture (497), and the IMR-32 human neuroblastoma cell line was determined to support JCV replication, which made it useful for propagating virus (6). JCV produced by persistently infected IMR-32 cells became cell culture adapted for growth in these cells (368, 372). Several other cell lines were established by fusing primary human fetal astrocytes with the glioblastoma cell line U-87MG (441). Alternatively, a pseudovirus system was created using SV40 large T antigen-transformed COS-7 cells expressing JCV structural proteins, which produced virus-like particles lacking viral genomes (451).

More recently, cultures of human fetal brain progenitor-derived astrocytes (PDAs) or progenitor-derived neurons (PDNs) derived from human fetal neural progenitor cells have been used to study viral gene expression, replication, and growth in specific glial cell types (334). These cells allowed further study of the molecular regulation of JCV by cell-specific factors in a more pure population of cells.

Although pathology of JCV occurs in tissues of the central nervous system, seroepidemiological studies show that more than half the global population is either transiently or latently infected with JCV (378), although there is heterogeneity among populations, even in nonindustrialized areas (305). Additionally, the percentage of seropositive individuals increases with age (247), and 10 to 30% of people shed JCV in the urine (299). Because direct infection of brain tissue is unlikely and would be exceedingly rare, dissemination by some more common route is probable. Further inquiry led to the observation that cells of the immune system, including hematopoietic progenitor cells and B lymphocytes, as well as tonsillar stromal cells and Schwan cells are susceptible to JC virus (19, 341, 342, 345). Additionally, it was found that JCV may remain latent in immune cells of the bone marrow (198, 201, 322, 484).

Despite the limited range of species and cell types permissive for JCV replication, JCV is ultimately a very successful pathogen, as illustrated by its wide dissemination but rare pathogenesis. This success is attributable to the tight regulation of the viral life cycle. The differential ability of JCV to bind, enter, transcribe gene products, replicate, and ultimately produce more infectious viral particles in various types of human cells is essential to the regulation and life cycle of the virus. The following sections discuss these aspects of the viral life cycle, with emphasis on stages that regulate the virus' ability to complete its life cycle in various cells.

Analysis of the Viral Genome

Similar to the case for all other polyomaviruses, the JCV genome is a closed circular supercoiled chromosome that is composed of “early” and “late” genes that are separated by the noncoding control region (NCCR), which contains the origin of replication (ORI), promoter, and enhancer elements (154) (Fig. 1 and 3). The early region is expressed de novo after infection and before DNA replication and is on the ORI-proximal side of the NCCR. Late genes are optimally expressed concurrently with or after DNA replication and are found on the ORI-distal side of the NCCR. The polyomavirus NCCRs are the most variable portions of the viral genome within a single virus as well as across genera of viruses (143, 151, 154, 267, 411, 446, 551).

The early-region sequences are transcribed counterclockwise from the NCCR and encode five proteins: the large T and small t antigens and splice variants called T′₁₃₅, T′₁₃₆, and T′₁₆₅ (153, 395) (Fig. 1). The JCV large T antigen is a 688-amino-acid nonstructural, multifunctional protein that regulates viral early gene transcription and is thus autoregulatory. Large T antigen also regulates the switch from early to late viral transcription, as well as viral DNA replication. Large T antigen interacts with a number of cellular proteins to support transcription and replication of the viral genome, and upon unregulated overexpression, it induces cellular malignant transformation. The 172-amino-acid small t antigen shares the open reading frame (ORF) start site of nucleotide 5013 (339), and thus its 5′ end, with large T, but it is differentially spliced (154) and contains a translation termination signal at nucleotide 4495 (339), as opposed to position 2603 for large T antigen (154), which results in different 3′ ends of small t and large T antigens. Small t antigen and the other T antigen splice variants also perform multiple functions to drive infected cells toward S phase and may contribute to gene expression and PML progression to various extents in the presence of different underlying disorders (211).

The late region is transcribed clockwise from the opposite strand of the genome, and is composed of the coding sequences for four proteins (154) (Fig. 1). The smallest protein, agnoprotein, has an open reading frame that codes for 71 amino acids, beginning at nucleotide 277 and terminating at nucleotide 492. The agnoprotein is not well understood but has been proposed to be a viroporin (478), as well as to interact with large T antigen to decrease viral DNA replication. It has also been demonstrated to interact with transcriptional activators and repressors to control gene activation as well as influence DNA repair pathways (101, 238, 437). The other three open reading frames code for the viral structural proteins VP1, VP2, and VP3. The open reading frames for the structural proteins overlap. The 354-amino-acid major capsid protein VP1 is found at the 3′ end of the late region (nucleotides 1469 to 2533), is the major structural protein, and functions in cellular binding and entry. The ORFs for the minor capsid proteins, VP2 and VP3, are found between the 3′ terminus of the agnoprotein ORF and the 5′ end of VP1. VP2 is a 344-amino-acid protein with an ORF between nucleotides 526 and 1560. VP3 is composed of the C-terminal 225 amino acids of VP2, with its coding region starting at nucleotide 883 and sharing the 3′ terminus of VP2 (154, 301).

The NCCR lies between the early and late coding sequences and contains the origin of replication (152, 154, 339). It contains extensive regions of homology with the polyomaviruses SV40 and BK virus, including two of the three T antigen binding sites found in SV40 (152), as well as a unique non-B DNA tertiary structure (15). The NCCR is thought to be the main determinant of cell type specificity and is composed of fairly well-conserved flanking regions that border the transcription start sites of the early and late coding regions, as well as a central region containing numerous transcription factor binding sites. The early-proximal side of the NCCR contains the preorigin and origin of replication. The NCCR varies greatly between isolates from PML patients. In addition, a sequence, known as archetype or CY, has been isolated from urine specimens from both PML patients and healthy people but is rarely found in PML brain tissue. The original sequence isolated from a PML patient is known as Mad-1, as it was isolated at the University of Wisconsin—Madison. Subsequent isolates have been named with various designations, often depending on their associated immunosuppression or locations of isolation, with Madison isolates being known as Mad-1, Mad-2, and so forth.

Replication of JCV Genomic DNA

JCV has a limited host replication range. There are two identified blocks to replication in nonpermissive cell types: early gene transcription and DNA replication. Activated late gene transcription is initiated only after DNA replication begins, although DNA replication is not required for late gene activity in vitro (52, 229). A number of host factors are required and may contribute to JCV early transcription. In the presence of T antigen isoforms, T antigen, the host DNA polymerase, and a number of other cellular proteins participate in JCV DNA replication.

Nuclear domain 10 (ND10) bodies (also called PML nuclear bodies, after the promyelocytic leukemia protein, which makes up the scaffold of this structure, or PODS, for PML oncogenic domains) are discrete nuclear loci characterized by accumulation of the promyelocytic leukemia protein, as well as Daxx, SP100, and a number of other cellular proteins (359). ND10 bodies are the nuclear substructures at which JCV DNA replication and capsid assembly occur (454). ND10 bodies are thought to regulate a number of cellular processes, as well as participate in the life cycles of numerous viruses (139). Like for many DNA viruses, the JCV genome can be detected at ND10 bodies after infection (452). ND10 bodies show a complex biology with regard to viral gene transcription and DNA replication (452). Numerous studies indicate that they play a role in cellular defense against DNA viruses, but in a number of cases, ND10 bodies seem to be positive regulators of viral replication (139). Multiple viruses, including polyomaviruses, disrupt or reorganize the ND10 bodies during the course of infection (215). Many viruses, including JCV, localize at, or in the vicinity of, ND10 bodies (139, 222, 452–454). During SV40 and BK virus infection, DNA elements have been found to localize in the vicinity of ND10 (222), and this localization is required for efficient DNA replication but not for transcriptional activation of SV40 (489).

The localization to ND10 bodies may promote JCV DNA replication in a number of ways. A number of transcriptional activating and DNA replication proteins can be found at ND10 bodies, including CBP/p300 and proliferating cell nuclear antigen (PCNA) (453). Thus, it is likely that JCV uses the ND10 bodies as a scaffold for DNA replication and viral assembly during early stages of infection, while late in infection, JCV causes the disruption of these replication sites (453) but does not reduce the total amount of the ND10 scaffold promyelocytic leukemia protein. Interestingly, T antigen, which is absolutely required for viral replication, also localized to the ND10 bodies.

Functional T antigen is required for JCV replication. This was confirmed by the observation that JCV containing mutations in the T antigen-coding region cannot commence a lytic infection. Both the SV40 and BKV T antigens can bind to the JCV origin and initiate a lytic infection (86). The SV40 T antigen has greater DNA binding activity and is more efficient in directing replication than the JCV T antigen (44, 86, 294). The SV40 and JCV T antigens are able to bind to the origin of replication in two of the three GAGGC sites (152). Sequences on the late side of second T antigen binding site have been shown to be extremely important to replication. These sequences adopt an unusual tertiary structure (15; reviewed in reference 301), and this structure may be required for efficient T antigen-directed viral DNA replication.

The kinetics of JCV replication indicate a slow process. Even in susceptible cells in which T antigen is already present, DNA replication is undetectable for several days (303). DNA replication can be detected at 3 to 5 days postinfection in susceptible cell types and continues for several weeks (142, 233).

In addition to the cell type restriction for JCV growth at the level of early transcription, the viral life cycle is also restricted by cell type differences in DNA replication. JCV can replicate in immortalized primate cell lines expressing the SV40 T antigen (185, 303), as well as in primate cell lines expressing the HIV transcriptional activating protein, tat (369, 370). However, rodent cell lines immortalized with JCV T antigen, monkey cells, or nonglial human cells that do not express T antigen cannot sustain efficient viral replication. JCV replication could occur in the monkey and human immortalized cells in the presence of T antigen, but in the rodent cells, even T antigen expression could not stimulate replication. Thus, it appears that transcription is regulated by cell-specific factors, while the restriction of DNA replication is most likely regulated by species-specific factors. These species-specific factors, which may be a component or components of the DNA polymerase (142), allow JCV DNA replication only in primates.

Viral DNA replication proceeds as early viral proteins accumulate. Large T antigen binds preferentially to site II, located in the viral DNA replication origin closest to first TATA box (see Fig. 3) in the NCCR (47), but it also binds cellular DNA (375). When large T antigen binds JCV DNA, it promotes the YB-1/Purα switch to viral late transcription. Large T antigen also interacts with host cell replication machinery to directly initiate replication.

Replication of JCV DNA has not been as well studied as that of SV40 DNA but is likely to be similar. Like in JCV, the SV40 genome is a closed circular supercoiled DNA molecule. To initiate DNA replication, large T antigen forms a double hexamer and acts as a helicase and complexes with topoisomerase I, DNA polymerase α, and replication protein A (RPA) (60, 141, 360). Large T antigen also contributes to elongation of the DNA chain by its interaction with DNA polymerase δ, proliferating cell nuclear antigen (PCNA), and replication factor C (273, 501, 529). Replication proceeds bidirectionally, similar to theta replication, and leads to two interlinked DNA circles, which are resolved through the action of topoisomerases I and II (reference 360 and references therein). It has been proposed that linear SV40 genomes can initiate rolling-circle replication, generating concatemers, and that this method of replication may explain some of the recombination seen in viral variants (105, 122, 459).

In order to promote an environment conducive to DNA replication, T antigen binds to cellular proteins and DNA to induce signals to drive quiescent cells toward S phase (64, 119, 237). Large T antigen has been demonstrated to exhibit numerous functions, including interaction with, and inhibition of, the retinoblastoma protein (pRb) (48, 490, 533) and p53 (110). Interaction with p53 also prevents apoptosis induced by checkpoint activation when cells aberrantly enter S phase (112). Additionally, large T antigen can promote viral replication in G₂-arrested cells by inducing DNA damage response pathways, and this function was related to binding of cellular DNA (375).

Small t antigen has been less well studied, but has been shown to interact with the RB family of proteins, as well as protein phosphatase 2A (PP2A) (45). The interaction of small t antigen with PP2A appears to prevent the dephosphorylation of the late protein agnoprotein, and this allows for greater viral replication (440). Reduction in levels of small t antigen or PP2A results in reduction of DNA replication (45, 440). Inhibition of the phosphatase activity of PP2A also drives the cell toward S phase, thus promoting viral replication.

Three alternative splice variants of T antigen exist, i.e., T′₁₃₅, T′₁₃₆, and T′₁₆₅, which share their N termini with large T antigen, and disruption of their donor splice site results in greatly reduced viral replication (498). Although much study remains to understand their functions, putative interactions with Rb family members have been identified, which also appear to drive cells into S phase (46).

While it is difficult to separate the effects of increased viral early gene expression from DNA replication, several proteins have been implicated in directly increasing viral DNA replication. The NFI family of proteins has been shown in cell-free DNA replication systems to increase DNA replication of adenovirus type 2 (50, 347) and the replication of SV40 in vivo (348). NFI proteins have also been extensively shown to modulate JCV replication in vivo (14, 235, 483). The isoform NFI-A, which is expressed in several nonpermissive cell types, has been shown to decrease viral late protein expression (409), while NFI-X (NFI-D) increases viral gene expression and is highly expressed in cells permissive to JCV replication (344). The cellular protein Purα is also likely to participate in viral DNA replication, as it can bind the origin of replication and has been shown to repress viral replication (71, 157). Additionally, there is evidence that the protein Sμbp-2 decreases viral DNA replication, while its smaller variant, GF-1, which encompasses only some of the helicase motifs of Sμbp-2, may increase viral replication (78).

It is likely that because of the repeated sequence and nonstandard secondary structure of the NCCR, recombination, deletions, and insertions occur during viral DNA replication. These recombinations, insertions, and deletions can explain the large variations of sequences of NCCRs derived from PML patients. The prototype Mad-1 NCCR contains two identical tandem repeats (two sets of a-c-e sequence blocks) followed by an f sequence block. Most PML-derived NCCR sequences contain some version of these repeats, with deletions and insertions in some cases. Archetype, or CY virus, which is found primarily in the kidneys and urine and often found in healthy subjects, does not contain repeats and generally has a regulatory region consisting of sequence blocks a-b-c-d-e-f. One hypothesis for viral transmission and evolution is that archetype-like virus is the circulating form and that deletions (generally of b and d sequence blocks) then occur, followed by duplication of remaining sequence. This then leads to a pathogenic form of the virus able to replicate efficiently in glial cells (24, 198). There is evidence that the archetype “d” region may be inhibitory to JCV growth in some cells so that its deletion allows productive infection of other cells (173).

Alternatively, since archetype virus is rarely found in tissue outside the kidney, it is possible that prototype-like viruses are transmitted and that sequences are deleted or duplicated through base mispairing and single-strand slippage or through various forms of DNA recombination. The “b” and “d” blocks of sequence can be found in the human genome (L. J. Marshall and E. O. Major, unpublished data). These could be incorporated through DNA “capture.” This hypothesis has been used to explain the generation of host-substituted SV40 variants (reference 459 and references therein) and may apply to JCV as well. Recombination of the JCV NCCR may also be explained by its interaction with cells of the immune system (see below).

Transcription of JCV Genes

The encapsidated JCV genome is closed, supercoiled, and circular and is bound by nucleosomes derived from the four core histones of the previous host cell, as determined for SV40 (12, 41, 302, 333, 518). Once the genome is delivered to the newly infected cell, it acquires the linker histone H1 and resembles cellular chromatin (302). In the nucleus, the JCV genome serves as a template for the host RNA polymerase II (pol II) transcriptional machinery. Transcription of the JCV early genes occurs in the absence of de novo protein synthesis and utilizes only host proteins. Much, if not the majority, of the cell type specificity of JCV within human cells occurs at the transcriptional level. Regulation of transcription is dependent on the sequence of the NCCR, as well as the availability of host transcription factors.

Mad-1 NCCR transcription factor binding sites include four Oct-6/tst-1/SCIP binding sites (528), two Purα binding sites (79), two YB-1 binding sites (79, 232), two LCP-1 binding sites (479), two GF-1 binding sites (78), four NFI binding sites (13, 14, 455, 483), and six Spi-B binding sites (314). The Mad-1 NCCR is composed of two 98-bp tandem repeats, each containing a TATA box (Fig. 3A). The transcription start sites for early and late transcripts have been mapped in several cell types and for several viral variants. In addition to specifying cellular permissiveness to JCV infection, viral NCCR sequence and host factor availability help to determine transcriptional start sites.

The 5′ termini of early mRNAs at 5 days postinfection of primary human fetal glial cells were mapped to nucleotides 122 to 125 (using the numbering system introduced by Frisque et al. [154]) by S1 nuclease analysis, which maps to within the late-proximal TATA box. This contrasts with the case for in vitro-transcribed RNA, which mapped to nucleotides 94 to 97 (231). In JCV-transformed hamster brain cells, the start site of major early viral RNA was mapped to nucleotides 5115 to 5124, approximately 25 bp downstream of the early-proximal TATA box, while a second, minor pair of early mRNA start sites was positioned approximately 25 bp downstream from the late-proximal promoter, by which they were probably positioned (310).

The Mad-4 NCCR has a deletion in the second repeat that eliminates the late-proximal TATA box and allowed for studies that determined the functional significance of multiple TATA boxes. The early mRNA start site of Mad-4 also mapped to nucleotides 5115 to 5124 in transformed hamster cells, but the minor start sites were eliminated, indicating that they were indeed positioned by the late-proximal TATA box (310).

Rodent cells are not permissive for JCV replication and are therefore transformed by JCV, so the transcriptional start sites may be different than in the natural human host. However, similar start sites were found in the human fetal glial cell line POJ, which constitutively expresses a functional JCV T antigen expressed by replication-defective JCV (309). In primary human fetal glial cells, at 3 to 5 days postinfection, the start sites of Mad-1 were found at nucleotides 5122 and 5082 by primer extension, whereas at 10 days postinfection, after DNA replication had begun, the early mRNA start sites shifted and were found at nucleotides 5012, 5037, 5047, downstream from the early-proximal TATA box, and at nucleotide 35, which is between the first and second TATA boxes (233). In another study utilizing both S1 nuclease and primer extension techniques in primary human fetal glial cells, early mRNA start sites were found for Mad-1 approximately 25 bp downstream of both TATA boxes, at nucleotides 89 to 92 and 5115 to 5125 (95). In that study, as in previous studies, the Mad-4 early start site at nucleotides 5115 to 5125 remained, but the site positioned in Mad-1 by the deleted TATA box was eliminated.

These data indicated that both TATA boxes were functional for early transcription and that they may vary in importance depending on the cell type infected. Although the second TATA box directs minor mRNA start site positioning, the major early mRNA start sites are downstream from the first TATA sequence, and the second TATA box may be dispensable. Many of the NCCR variants found in PML patients do not contain the second TATA box (90, 173, 317, 413). Recently, it has been shown that the Spi-B transcription factor binding sites in the second repeat can compensate for the loss of the second TATA box (314). Additionally, NCCR variants lacking repeat sequences show greatly reduced early transcriptional activity in comparison to both Mad-1 and Mad-4 (173). Thus, sequences and transcriptional activator binding sites that are important for early gene transcription are present throughout the viral NCCR and contribute to viral early transcription, even in the absence of a second TATA box.

In human fetal glial cells, at 17 to 19 days postinfection, several major and minor transcriptional start sites for Mad-1 late mRNA were found to span a large region of the viral NCCR, covering approximately 250 bp between nucleotides 5114 and 242, which are on either side of the repeats (95, 230). These start sites appear to be positioned not by either TATA box but rather by the sequence TACCTA, which was approximately 30 nucleotides upstream from the minor start site at nucleotides 90 to 98, as well as the major start site at nucleotides 198 to 203 (230). The TACCTA sequence can function as a surrogate TATA box, as has been shown in SV40 (53, 355).

Host transcription factor availability is the determining factor in both the start sites for early transcription, as well as the quantity of T antigen produced. Although NCCRs containing repeats (such as Mad-1 or Mad-4) and variants isolated from PML strains have greater transcriptional activity in PDA cells (173), both the archetype and various PML isolates show increased transcriptional activity in glial cells rather than cells of nonglial origin (23, 464). Once T antigen is present, the difference in replication fitness between different variants of JCV becomes much less apparent (23). Therefore, the ability of the virus to transcribe the early side of its genome is a major determinant of cell type specificity of the virus and has been the focus of much of the research on viral transcription.

Unlike other human DNA-containing viruses, such as herpesviruses, JCV does not bring transcriptional activating proteins into a newly infected cell. Thus, early transcription is directed entirely by host cell factors. The JCV NCCR contains binding sites for a number of transcription factors and transcriptional repressors. As shown in Fig. 3, the proteins NFI-X (344, 410), DDX-1 (475, 476), LCP-1 (479), HIF-1α (390), BAG-1 (118), NFAT4 (311), NF-κB (405, 435), GF-1 (78), SP1 (190, 191, 242), and Spi-B (314) have all been proposed to bind to certain variants of the JCV NCCR and activate early transcription in various cell types, while NFI-A (409), c-jun (240, 410, 432), c-fos (240), SF2/ASF (439), and C/EBPβ (425) have been proposed to repress early transcription. Of these, the most well-studied JCV-transcription factor interactions have been with members of the NFI family.

The NFI family of cellular DNA binding proteins is critical to JCV transcription and replication (344, 409, 410). These proteins were first identified as part of the minimal set of proteins required for in vitro replication of adenovirus DNA (106, 176, 351–353). Three NFI binding sites have been demonstrated in the JCV regulatory region (NCCR) by sequence homology and DNase protection assays (14, 483), and one potential, uninvestigated site exists, as identified by sequence homology. The confirmed sites have been alternatively labeled in order from the early side of the genome as NFI-A and NFI-B (285) or from the late side of the genome as NFI I, II, and III. In order to avoid misunderstanding, the second convention is less confusing, as four NFI genes exist, NFI-A, -B, -C, and -X (alternatively called -D) (176). The two identical sites in the 98-bp palindromic repeat element (NFI II/III) were shown to be more important for early gene transcription than the unique third element on the late side of the NCCR (NFI I) (260, 455). These sites were also shown to be more important for late gene expression (259). Additionally, these sites appear to contribute to the cell type specificity of JCV, as they are bound by different proteins in different cell types (13, 14, 220, 259, 260, 409, 410, 483).

DNase I footprinting experiments demonstrated that various tissues and cell types contained different factors that bound to the JCV NCCR at dissimilar sites (482). This observation was explained when the four NFI genes were discovered, each with multiple splice variants (176). The dimerization, DNA binding, and DNA replication domains of NFI proteins are found in the N terminus and are separable from the transcriptional activating domains (176). All four NFI genes share homology at the N terminus and differ at the C terminus, which is responsible for transactivation and repression activity (176). NFI proteins can homo- and heterodimerize and compete for identical binding sites. The character of the NFI dimer may influence transcriptional activity. This could explain why overexpression of NFI-X confers the ability to support increased viral activity in cell types normally nonpermissive for JCV (344), while overexpression of NFI-A decreases the ability of permissive cell types to support JCV infection (409). Additionally, NFI proteins also regulate transcription from a number of genes important in cells of neuronal origin (324).

Members of the activating protein 1 (AP-1) family play an important regulatory role in JC virus transcriptional activation (13, 240, 410, 432). NFI binding to and activation of JCV are reduced by the presence of c-jun (13, 410). This appears to be due to the overlapping AP-1 and NFI binding sites in the JCV NCCR, implying that c-jun physically blocks NFI-induced activation. Interestingly, this juxtaposition of AP and NFI binding sites occurs at numerous genes associated with central nervous system cells, such as those for glial fibrillary acidic protein (GFAP), a cytoskeletal marker for astrocytes, and myelin basic protein (MBP), a component of myelin produced by oligodendrocytes (13). Thus, it is likely that activation of JCV is controlled by access to DNA binding proteins available in cells of the nervous system and that a common regulatory mechanism of JCV and these genes may exist. Further research will yield a greater understanding of the interplay between these DNA binding factors, the JCV regulatory region, and genes important for neuronal and glial differentiation.

Both NFI and AP-1 family members interact with large T antigen. NFI has been shown in several studies to increase early and late gene expression in a T antigen-dependent manner (14, 259, 260, 285), as well as to contribute to increased viral replication (344, 409, 410, 465). The AP-1 members c-jun and c-fos have been shown to physically interact with large T antigen and suppress its activation of early genes, as well as viral DNA replication (240). Thus, AP-1 family members and NFI family members appear to make up an antagonistic switch system for JCV gene expression and DNA replication.

This system may be similar to a better-characterized switch in the JCV life cycle. The cellular proteins YB-1 and Purα interact with the viral large T antigen to regulate the switch from early to late gene expression (77, 79, 232, 434, 436, 437). Purα is a strong activator of early gene expression and binds the viral lytic control element (LCE) (77, 79). As T antigen accumulates, it facilitates binding of YB-1 to the LCE, and together YB-1 and T antigen increase the displacement of Purα from the viral promoter. YB-1 and T antigen stimulate late gene expression (77, 79, 232, 436), and thus Purα, YB-1, and T antigen work as a genetic switch to shift gene expression from viral early to late genes.

Activated late gene expression requires T antigen and occurs concurrently with DNA replication but, at least in the case of SV40, does not require DNA replication to proceed (229). The large T antigen ORI binding function is not necessary for activation of late transcription of SV40 (229). Instead, T antigen promotes late transcription by interacting with components of the basal transcription machinery, including TATA binding protein (TBP), TBP-associated factors (TAFs), and transcription factors, including Sp1 (239). T antigen may also function directly as a TAF (92).

A number of DNA binding proteins have been implicated in regulation of viral late transcription. Egr-1 (424), HIF-1α (390), GF-1/Sμbp-2 (78), BAG-1 (118), and NFAT4 (311) have been shown to activate late gene transcription, while C/EBPβ (425) and GBP-i (402) appear to function as transcriptional repressors. Subunits of NF-κB have been shown to increase late gene expression (328, 435) and can increase viral expression in response to tumor necrosis factor alpha (TNF-α) stimulation (539). Subunits of NF-κB also interact with YB-1 (403), which stimulates the switch from early to late gene expression.

Additionally, although the functions of the late viral protein agnoprotein remain to be elucidated, it has been posited to interact with YB-1 and may modulate its activity (438). Agnoprotein may also interact with large T antigen to reduce T antigen enhancement of late gene expression (433).

The best-characterized cellular protein known to stimulate viral late gene expression is Tst-1, also referred to as Oct-6 or SCIP. Oct-6/Tst-1/SCIP is a POU domain protein known to function in neuronal development (209, 266, 527), thus potentially contributing to the cell type specificity of JCV transcription. Oct-6/Tst-1/SCIP overexpression increases both early and late gene expression (528). Oct-6/Tst-1/SCIP binds to large and small T antigens in vitro and can synergistically increase both early and late gene expression in the presence of large and small T antigens (416).

Initial Infection and Latency

Although JC virus has been known to be the causative agent of PML since the 1970s, the routes of initial viral transmission and subsequent dissemination to the brain remain to be fully elucidated. Without the provision of exogenous T antigen, JCV was known to replicate only in human cells of glial origin in culture. A hematogenous route of infection of the CNS seemed likely after JCV was discovered to interact with B cells in the brain, periphery, tonsils, and bone marrow and to replicate at low levels in B cells (22, 201, 300, 301, 421, 494).

Several years later, it was shown that JCV could infect tonsillar stromal cells and hematopoietic progenitor cells, as well as primary B cells (341, 345). In addition, evidence was provided that one of the initial sites of infection could be stromal cells of the tonsils (342). These discoveries led to a model in which primary infection most likely occurs in either stromal or immune cells of the upper respiratory system, either through respiratory inhalation or orally through ingestion of virus-contaminated material, possibly from excreted virus in the urine (37). The virus is then trafficked to the bone marrow and kidneys by infected lymphocytes, where it can persist for the life of the host. Upon immunosuppression or a change in immune cell trafficking, the virus mobilizes from the bone marrow and crosses the blood-brain barrier, either alone or in conjunction with a B cell. Once oligodendrocytes become infected, lytic infection begins (201). It is also possible that virus in the kidney replicates at high copy levels, escapes into the peripheral circulation, is taken up in lymphoid tissues such as the bone marrow, and then undergoes rearrangements of the NCCR.

Alternatively, the brain or kidney may serve as a site of latency (104). JCV DNA, but generally not protein, has been found in the brains of both healthy and immunocompromised patients without PML or other neurological disorders (31, 107, 386, 485). This suggests that JCV has access to the CNS before disease onset and may travel to, and nonproductively infect, the brains of some immunocompetent individuals. It is possible that after initial infection by JCV and viral dissemination, possibly through hematopoietic precursors or B cells, the virus reaches glial cells of the brain, where it remains latent. This observation leads to model in which JCV traffics to the brain and remains latent in the CNS. The virus would remain latent unless changes in the NCCR, which may occur before or during latency in the brain, and available binding factors occurred in the presence of immunosuppression. However, if these events occur, then upon a reduction in immune surveillance and control due to compromise or modulation of the immune system, JCV may reactivate in situ and cause PML. This pathway, however, does not address the very low incidence of PML in allograft recipients who are immunosuppressed for substantial periods for graft protection. In both models of viral latency, although the site of latency may differ, similar events must occur for progression to PML.

Immune Control of JCV: Humoral and Cellular Responses to Infection

Approximately 60 to 80% of humans produce antibodies against JCV, indicating that the majority of the population has been exposed to the virus (247). These rates vary greatly among populations and age groups (305). Additionally, at any given time, approximately one-fifth of the population sheds JCV in urine (299). Only a very small fraction of these individuals become ill, however, and this occurs only in the presence of underlying changes to the immune system. Thus, in the majority of cases, JCV infection is controlled by the healthy immune system.

Several observations indicate that the cellular immune response plays a vital role in control of the virus. PML is an AIDS-defining illness, occurring in 3 to 5% of HIV-infected individuals (299). Before the advent of the AIDS pandemic, PML was extremely rare, indicating that a reduction of CD4⁺ T cells due to HIV infection leads to lack of immune control of JCV. Additionally, non-HIV-associated CD4⁺ T cell reduction due to idiopathic CD4⁺ T lymphocytopenia has been associated with a number of cases of PML (179, 396). Other studies have implicated an impairment of T cell responses in the development of PML (526), while a cytotoxic T lymphocyte (CTL) response has been associated with greater control of JCV and longer PML survival rates (129, 249, 250, 278, 321). The use of HAART has reduced the rate of PML in HIV-infected individuals, further indicating an important role for a cellular immune response to JCV in control of infection (10, 136).

In contrast, the humoral immune response has not been shown to control JCV infection (249, 526). In fact, the virus seems to have adapted to replicate and disseminate, possibly through B cells and their progenitors. JCV is known to remain intranuclear once assembled, which may allow viral escape from immune recognition.

Potential Viral DNA Recombination and Replication in Cells of the Immune System

In addition to serving as a potential site of viral latency, B cells may play an important role in the pathogenesis of PML. Since it has been posited that the viral genome recombines and/or rearranges during DNA replication, an attractive model is that these events occur in B cells, which can undergo V(D)J recombination. This hypothesis is bolstered by the observation that diverse viral NCCRs, including archetype-like and prototype-like NCCRs, have been found in the blood and bone marrow (214, 322, 484).

Recombination that results in prototype-like viral NCCRs is associated with increased viral activity in glial cells (173). JCV infection has also been shown to upregulate the DNA damage response (101, 102), and high antibody titers to JCV are associated with increased chromosomal damage in lymphocytes (269, 340). JCV infection of cells in culture as well as cultured lymphocytes also results in a high degree of chromosomal damage (356, 357). These damaged chromosomes are similar to those seen in SV40-infected cells and may be the source of some of the sequence blocks found in PML-associated viral NCCRs, such as in Mad-1. Thus, viral recombination may be explained by chromosomal damage induced by JCV in cells in which recombination and DNA repair mechanisms are active, as may be the case for SV40 (459). These changes may lead to acquisition of transcription factor binding sites in the NCCR that are important for pathogenesis. A recent example was described in patients receiving infliximab, where an archetype-like NCCR contained sequences that led to TATA box-associated Spi-B sites known to be important for viral replication, while JCV in the urine contained an archetype NCCR sequence (32). Additionally, as B cells mature, different transcription factors that play a role in increased viral proliferation are upregulated.

As early as the 1990s, it was recognized that there are DNA binding proteins that are common between B cells and glial cells (300, 421) but that do not exist in T cells (421). At least two factors shown to be important in JCV transcription and regulation, NFI-X and Spi-B, have been shown to be upregulated in B cells, glial cells, and hematopoietic progenitor cells in which JCV can replicate (314, 334, 344). Evidence that changes in transcription factors can affect viral transcription as B cells mature is increasing, particularly in light of the observation that natalizumab treatment upregulates factors involved in B cell differentiation, including Spi-B (281).

Viral Pathway to the CNS

B cells may also carry JCV across the blood-brain barrier. Evidence for this is found in the fact that PML was first associated with B cell lymphoproliferative disorders (57, 198) and that natalizumab treatment-associated PML occurs concurrent with mobilization of lymphocytes from the bone marrow to the periphery (406). Additionally, HIV depletion of lymphocytes in the periphery may lead to mobilization of lymphocytes from the bone marrow to the periphery, and PML may be “unmasked” after the reconstitution of the immune system in the periphery by HAART treatment (457).

In addition to mobilization of B cells into the periphery, JCV must cross the blood-brain barrier to initiate infection of oligodendrocytes. B cells can carry JCV to the blood-brain barrier, where it may cross as free virus. JCV may also infect microvascular endothelial cells and thereby cross into the brain (75). Alternatively, B cells may carry JCV across the blood-brain barrier. For instance, in HIV infection, in which a relatively high percentage of infected patients develop PML, macrophage chemoattractant protein 1 (MCP-1) is upregulated, which increases the permeability of, as well as lymphocyte migration across, the blood-brain barrier (530). Infected B cells have been found in the CNS of a patient with PML (300). Additionally, infected B cells can transmit JCV to glial cells in culture (73).

The primary working hypothesis for development of PML is that at least four events must occur for latent JCV to cause lytic infection of the oligodendrocytes in the brain: (i) the host immune system must be compromised or altered, (ii) the viral NCCR must acquire changes that increase viral transcription and replication in both B cells and glial cells, (iii) DNA binding factors that bind to recombined NCCR sequence motifs must be present and/or upregulated in infected hematopoietic progenitor, B cells, and/or glial cells, and (iv) free virus or virus in B cells must cross the blood-brain barrier and be carried into the brain, where virus is passed to oligodendrocytes and lytic infection takes place. Once the virus is in the brain of the susceptible (immunocompromised) host, PML occurs. These events may occur in the bone marrow, in CD34⁺ lymphocyte precursors or B cells in the periphery, or in the brain.

Risk Factors in the Development of PML

Primary infection with JCV is asymptomatic and occurs in immunocompetent individuals early in childhood. Thus, the major risk factor for developing this infection is immune compromise. This includes patients with cancers that involve the lymphoid system, such as lymphomas, or patients who are on long-term immunosuppressive therapy for treatment of cancer or autoimmune diseases. Patients who undergo organ transplant are also at risk due to the need for chemotherapy to prevent organ rejection (325). Some elderly patients may also develop PML, presumably due to compromise in the cellular immune responses associated with the process of aging (164). The recent development of monoclonal antibodies that target different arms of the immune system has also been associated with PML. The majority of these cases are due to the use of natalizumab (anti-α4 integrin), which prevents T cell trafficking into the brain and is used for treatment of multiple sclerosis, and rituximab, which targets B cells (anti-CD20). However, cases have also been reported with alemtuzumab (anti-CD52), infliximab (anti-TNF), efalizumab (anti-CD11a), and ibritumomab (anti-CD20) (227). Immune compromise alone may not be sufficient to cause PML. It is possible that other host factors may also play a role. For example, in one study, sequencing of the p53 gene, exon 4, showed heterozygosity (Arg-Pro) at codon 72 in five of six PML patients (394).

Neuropathology of PML

The central feature of the pathology associated with PML is the infection of the oligodendrocyte with JCV, which leads to lysis of the cell. The infection spreads to surrounding oligodendrocytes and results in focal destruction of myelin. The infected oligodendrocytes have collections of viral particles in the nuclei, which give the appearance of inclusion bodies and loss of chromatin structure upon examination by light microscopy. The size of the nucleus may also increase by as much as 2- to 3-fold. Morphologically normal oligodendrocytes may also be infected with the virus, as seen by immunohistochemistry or in situ hybridization. These cells are usually present in areas where the myelin appears to be normal. The multifocal nature of the lesions suggests a hematogenous spread of the virus to the brain. To a lesser extent, astrocytes are also infected with JCV. These cells appear large, and the nuclei are irregular and lobulated and appear premitotic but do not become neoplastic. These cells have been described using the term “bizarre.” Reactive astrocytes are also present, which is a nonspecific finding. Although neurons themselves are rarely productively infected by JCV, demyelination leads to axonal dysfunction, and the demyelinated axon is susceptible to injury by cellular products released by the glial cells. Axonal injury can result in a retrograde loss of the neuronal cell body. Loss of neurons is likely permanent.

Invading macrophages are commonly seen in the centers of lesions. They act as scavengers and are often laden with myelin debris in the sites of lesions. Macrophages and microglia are not infected by JCV. In PML patients with HIV infection, there can be massive necrotic lesions with infiltration by HIV-infected macrophages (536).

Lymphocytes are not typically seen in PML lesions except if there is restoration of the immune system leading to an immune reconstitution inflammatory syndrome (IRIS). Under these circumstances, CD8⁺ T cells are the predominant cell type and are present in perivascular regions at sites distant from areas with JC virus infection as well as in focal collection in the parenchyma in proximity to JCV-infected cells (511, 544). The presence of cytotoxic T cells against JCV is considered to be a good prognostic sign. It is postulated that the rapid restoration of the immune system may lead to an expansion of activated T cells, which may contribute to the massive inflammatory response seen in patients with IRIS and can result in significant morbidity and mortality.

Clinical Features of PML

JC Virus Granule Cell Neuronopathy and Other JCV-Associated Neurological Disorders

While the typical characteristics of PML are those of a white matter disease, productive infection of granule cell neurons by JCV has been reported. Changes in the cerebellar granule layer during PML have been observed for over 50 years (419), and these include enlarged and hyperchromatic nuclei (420), which are found in approximately 5% of PML patients. For many years it was unclear whether these cells were directly infected with JCV or were damaged collaterally as a result of the destruction of glial cells by JCV.

In 2003, productive infection by JCV of granule cell neurons in the cerebellum in an HIV-positive patient with PML was described (127). This individual presented with pyramidal tract and cerebellar dysfunction. Autopsy revealed classic PML in the frontal lobe and productively infected neurons expressing viral proteins in the internal granule cell layer, as demonstrated by immunohistochemistry and electron microscopy. Infected neurons which did not express viral proteins were also detected by in situ hybridization.

Subsequently, JCV was found in the brain of a patient with cerebellar atrophy but no detectable white matter PML lesions (251). This pathology, termed JC virus granule cell neuronopathy (JCV-GCN), was proposed to be a novel clinical syndrome distinct from PML. JCV-GCN has been since described in both HIV-positive and HIV-negative patients (175, 188, 228, 448, 487). In the original case study, it was determined that the NCCR was type IS, with no “b” and “d” sequence blocks as found in archetype and no repeat structure but with some other small insertions that did not correspond to sequences found in any known JCV isolate. A more recent case involving an AIDS patient with cerebellar atrophy also showed rearrangement of the NCCR, also with a type IS/IIS arrangement (with no sequence block “b” and only a partial piece of block “d”). Comparison of CSF-isolated virus and cerebellar virus NCCRs showed differences and changes in transcription factor binding sites (426). Thus, it appears that alternative transcription factor binding sites may play a role in JCV-GCN, further demonstrating the importance of the NCCR sequence in JCV cell type specificity.

Alternatively, entry into neurons or postentry steps such as transport, uncoating, or assembly may be changed by differences in JCV capsid proteins. In multiple JCV-GCN case reports, deletions and frameshift mutations in the C terminus of the JCV VP1 gene have been found (93, 94) when matched to the Mad-1 variant as well as to a hemispheric white matter isolate from the index case of JCV-GCN.

JCV-GCN is a productive infection of granule cell neurons and should be considered in cases of cerebellar atrophy. Symptoms are indicative of subacute or chronic cerebellar dysfunction, including gait abnormalities, dysarthria, and incoordination (486). MRI findings of cerebellar atrophy in the absence of white matter lesions and positive PCR of the CSF indicate the possibility of JCV-GCN (486). Diagnosis is complicated by the possibility that both JCV-GCN and classic PML pathologies can occur simultaneously. The finding of JCV-GCN in conjunction with classic PML requires cerebellar biopsy showing a lytic infection of granule cell neurons. It is possible that JCV-GCN, or productive infection of neurons in general, is a frequent complication in classic PML cases, with a report of 79% of PML cases showing infection of granule cell neurons (542). It is also possible that classic PML, with lesions of undetectable size, may be present in the reported cases of JCV-GCN.

JCV protein expression in cortical neurons neighboring white matter lesions of PML patient samples has also been detected, although the predominant expression was of T antigen, indicating the possibility of an abortive or restrictive infection in these cells (545). In one case, termed JCV encephalopathy, lytic infection by JCV of cortical pyramidal neurons with limited demyelination was described (543). Another rare pathology of JCV, JCV meningitis, has also been reported (40, 512). While these case reports are of interest in that they demonstrate a possible expansion of permissive cell types and clinical pathology of JCV, this review focuses on classical PML and PML-IRIS, as this has been the focus of the majority of research on JCV. More detailed information on rare JCV-associated diseases can be found in a recent review article (486).

Potential Association of JCV with Human Cancer

In addition to its role in the development of PML, several studies have underscored the ability of JCV to transform cells in culture and induce tumors of neural origin in several experimental animal models, such as golden Syrian hamsters and rats (114, 287, 288, 374, 523).

Early studies also confirmed that JCV caused tumors in nonhuman primates, specifically New World monkeys, including owl and squirrel monkeys. While several different kinds of tumors form in JCV-inoculated rodents, JCV-induced tumors in owl and squirrel monkeys are almost exclusively gliomas. These gliomas develop 14 to 36 months after intracranial inoculation with JCV, with a long period of asymptomatic “latent” infection followed by rapid tumor growth and progression, neurological impairment, and death (200, 287, 288, 329). New World monkeys have been used to study the immune response to JCV-induced tumors (524), as well as to develop radiographic diagnostic procedures for human astrocytomas (199).

Most JCV-induced brain tumors in monkeys have integrated viral DNA (335), often in a head-to-tail configuration of at least two copies (336), and express the large T antigen (298). T antigen did not bind the p53 tumor suppressor protein (304). Interestingly, in another case, JCV T antigen was found to bind p53, indicating that there were structural differences between T antigen in this tumor and that from the previous study (308). This was also the first case of p53 described in a primate brain tumor. In this study, a glioma was induced in an owl monkey inoculated with JCV, and recipient owl monkeys were inoculated intracranially with a tumor cell suspension of the explanted glioma tissue. One monkey (termed owl monkey 586), developed an astrocytoma, which, upon explant, was shown to have both integrated and free viral DNA with an NCCR corresponding to the Mad-4 variant. These cells also produced JCV T antigen which bound p53 and produced infectious virus particles. Studies of gliomas in New World monkeys demonstrated the possibility that JCV could cause gliomas in nonhuman primates and that, at least in rare cases, these transformed cells could produce infectious virus. These findings provided an impetus to determine whether an association between JCV and human cancer could be found.

Recent studies point to the association of JCV with human cancer, including brain tumors, colon cancer, and others, but it is important to note that there is a substantive variation between different laboratories as to the frequency of association of cancer and the presence of JCV (170, 423). It is now evident that the oncogenic activity of JCV is closely linked with the expression of the portion of its genome carrying the early gene, whose product, large T antigen, has the capacity to associate with several important cellular proteins that are essential for the control of cell growth and proliferation (117, 534). Direct evidence for tumorigenicity of T antigen comes from studies of transgenic animals encompassing the JCV early genome, demonstrating that in the absence of viral replication, expression of T antigen induces a broad range of tumors of neural origin, including tumors of glial origin, primitive neuroectodermal tumors (PNETs), abdominal neuroblastoma, malignant peripheral nerve sheath tumors (MPNSTs), and pituitary tumors (114, 145, 256, 257, 456, 460). Histological and molecular studies of tumors from these transgenic mice revealed the interaction of T antigen with well-characterized tumor suppressor proteins, including p53 and members of the pRb family, in these tumors and dysregulation of related cell cycle controllers, including cyclins, cdks, and p21^WAF (256). Furthermore, the association of T antigen with other tumor suppressor proteins, including the neurofibromatosis 2 gene product (merlin or NF2), has been observed in JCV transgenic mice with MPNSTs (456).

Extensive study of tumors derived from T antigen transgenic mice have elucidated several other pathways that may contribute to the development of PNETs caused by JCV. In one series of studies, it was demonstrated that T antigen, by association with β-catenin, results in the stabilization of β-catenin and its nuclear localization in the tumor cells. Interestingly, upregulation of the expression of several targets for β-catenin was observed in these cells, including cyclin D and c-myc (158). On the other hand, in the presence of T antigen, the cross-communication of β-catenin with G protein kinases, including Rac, in the cell membrane was found to activate alternative oncogenic signal transduction pathways involving JNK, Ras, NF-κB, and others (39).

In addition to β-catenin, JCV T antigen also interacts with insulin receptor substrate-1 (IRS-1), a key mediator of the insulin-like growth factor-1 (IGF-1) pathway. This interaction promotes nuclear localization of IRS-1 in mouse medulloblastoma cell lines that are positive for T antigen (265). While the exact biological importance of this event remains to be determined, recent studies suggest a role for nuclear IRS in chromosomal instability (414, 496). Thus, current evidence indicates that JCV T antigen, by altering the biological activities of several tumor suppressor proteins, as well as proteins involved in multiple signaling pathways, can initiate a cascade of events that leads to uncontrolled cell proliferation in experimental animals containing the JCV genome and in tumor cells derived from these animals.

Several reports indicate that different forms of human cancer, most notably medulloblastoma, are positive for the presence of the JCV genome and the expression of JCV T antigen as well as the late auxiliary protein agnoprotein, but not viral capsid proteins, in the tumor tissue (113, 255). These observations remain somewhat controversial, as other reports indicate that JCV is not the causative agent of these tumors (186, 241, 349, 509). Interestingly, p53 was reported to be colocalized in the nucleus with T antigen, suggesting that the interaction of T antigen with p53 may abrogate the role of p53 in control of cell proliferation. In addition, IRS-1 was found in the nuclei of these tumor cells, as was also the case for tumors arising in mice that are transgenic for the JCV early region (115). The detection of JCV agnoprotein, which exhibits the ability to dysregulate the cell cycle via p53 and cyclin B and to impair DNA repair through Ku70/80 (100, 101), has also been reported in human tumor cells (113). Agnoprotein was reported to be localized in the perinuclear region, as is also observed in PML (236).

The JCV genome has also been reported for several tumors of nonneural origin, including colorectal cancer, gastric cancer, esophageal carcinoma, and lymphoma (65, 69, 111, 116, 131, 132, 157, 193, 261, 280, 282, 340, 350, 365, 417, 447, 449, 450, 513, 549), although it should again be noted that there are also reports to the contrary (163, 291, 363). Consistent with observations in tumors of neural origin, examination of these tumor cells showed expression of T antigen, and in some cases agnoprotein, in tumor cells, where it was colocalized with p53 and β-catenin (65, 111, 116, 131, 261). While the importance of these observations in regard to the initiation of transformation or in maintenance of tumors remains to be established, the detection of JCV viral proteins in these tumor cells opens the possibility that JCV T antigen and possibly agnoprotein may accelerate the development and progression of tumors by inactivating tumor suppressors and/or dysregulating signaling pathways.

The evidence outlined above concerning the association of JCV with human cancer and the parallel molecular findings observed in JCV-induced tumors in experimental animal models support a potential role for JCV in the pathogenesis of human tumors harboring JCV DNA sequences and expressing JCV oncoproteins. Nevertheless, consensus concerning the extent of involvement of JCV with human tumors is still lacking, and this is presumably due to differences in technical issues that exist between different laboratories, which have recently been reviewed in detail (117). It is possible that the expression of T antigen in JCV-positive cells may not persist during the course of tumor cell maturation and progression. In fact, several studies have shown that T antigen-positive cells may lose expression of T antigen after extensive passage in culture. The loss of T antigen expression appears to have no significant impact on the doubling time of the cells. Interestingly, the gene sequences for T antigen remain intact in these cells, suggesting that loss of T antigen may result from other mutations in the JCV genome, modification of the viral DNA and/or RNA, or rapid turnover of T antigen due to its degradation. These observations have led to the speculation that transient expression of T antigen reprograms pathways that control cell growth and proliferation by dysregulating factors involved in the control of the cell cycle and chromosomal stability such as p53. Examination of tumors from JCV transgenic mice indicates that expression of T antigen is observed in only a fraction of tumor cell nuclei, suggesting extinction of T antigen expression in a subpopulation of tumor cells due to genomic instability or acquired mutations that promote uncontrolled cell proliferation (535). Similarly, it is conceivable that T antigen may also be downregulated in human tumor progression. While possible early events in the genesis of tumors containing the JCV DNA sequence have yet be elucidated, it may be envisioned that JCV involvement in tumorigenesis may be caused by abortive infection, a rare event, which then leads to clades of cells that, upon T antigen and perhaps agnoprotein expression, enter the cell cycle, progressively grow, and become transformed. In this respect, T antigen may function by targeting tumor suppressors such as p53, pRb and NF2, and signaling factors, including IRS-1 and β-catenin, as determined in the molecular experiments with JCV early transgenic mice and human tumors described above. In this way, JCV may initiate the formation of, and perhaps contribute to the progression of, tumors of neural origin. Thus, further investigation of the possible role of JCV in human brain tumors is warranted, and to fully investigate a role for JCV with neural and nonneural tumors, large-scale epidemiological studies are necessary.

Michael W. Ferenczy is a postdoctoral research fellow in the Laboratory of Molecular Medicine and Neuroscience at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH). He obtained his Ph.D. in molecular virology and microbiology in the laboratory of Dr. Neal DeLuca at the University of Pittsburgh School of Medicine, where he studied the role of the transactivating protein ICP0 in epigenetic control of herpes simplex virus 1 transcription. His current research interests involve the role of the NFI family of proteins in the JCV life cycle, as well as JCV-HIV interactions that lead to PML.

Leslie J. Marshall is a postdoctoral research fellow in the Laboratory of Molecular Medicine and Neuroscience at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH). She obtained her Ph.D. in microbiology and immunology in the laboratory of Dr. David Ornelles at Wake Forest University, where she studied the molecular regulation of adenovirus latency in T lymphocytes involving the leukemia-associated protein RUNX1. Her current work as a research fellow in the laboratory of Eugene Major at NIH led to the novel observation that the B cell transcription factor Spi-B is expressed in human glial cells and is involved in the molecular regulation of JC virus gene expression in these cells. Her studies continue to support an important role for JC virus-infected lymphoid cells in the molecular pathogenesis of progressive multifocal leukoencephalopathy.

Christian D. Nelson is a postdoctoral research fellow in the laboratory of Professor Walter Atwood in the department of Microbiology, Cell Biology, and Biochemistry at Brown University. He obtained his Ph.D. in comparative biomedical sciences in the laboratory of Professor Colin Parrish at Cornell University, where he studied antibody neutralization and the in vitro stability and uncoating of canine parvovirus. His current research interests involve mapping the infectious entry pathway of JC polyomavirus and developing novel antiviral compounds that inhibit JC polyomavirus replication.

Walter J. Atwood is Professor and Vice Chair of the Department of Molecular Biology, Cell Biology, and Biochemistry at Brown University. His laboratory focuses on invasion of host cells by human polyomaviruses. His early work as a graduate student with Len Norking at the University of Massachusetts at Amherst led to the identification of the cellular receptor for SV40. As a postdoctoral fellow with Eugene Major at the National Institutes of Health, Dr. Atwood began work on the human polyomavirus JCV, focusing on transcriptional regulation of the virus in glial cells and B cells. Since joining the faculty of Brown University in 1995, Dr. Atwood has focused on understanding how human polyomaviruses engage host cell receptors to establish infection. His work has led to several major discoveries, including the characterization of the sialic acid-dependent infectious mechanisms for both JCV and BKV, characterization of the modes of virus entry into cells for both JCV and BKV, and identification of a JCV receptor complex.

Avindra Nath received his M.D. degree from Christian Medical College in India in 1981 and completed a residency in neurology at the University of Texas Health Science Center in Houston, followed by a fellowship in multiple sclerosis and neurovirology at the same institution and then a fellowship in neuro-AIDS at NINDS. He held faculty positions at the University of Manitoba (1990 to 1997) and the University of Kentucky (1997 to 2002). In 2002, he joined Johns Hopkins University as Professor of Neurology and Director of the Division of Neuroimmunology and Neurological Infections. He joined NIH in 2011 as the Clinical Director of NINDS, the Director of the Translational Neuroscience Center, and Chief of the Section of Infections of the Nervous System. His research focuses on understanding the pathophysiology of retroviral infections of the nervous system and the development of new diagnostic and therapeutic approaches for these diseases.

Kamel Khalili is a Professor in the Department of Biology, as well as the Department of Microbiology, at Temple University and holds an adjunct professorship at the University of Milan in Milan, Italy. He received his Ph.D. in microbiology from the University of Pennsylvania School of Medicine, where he studied regulation of human actin genes in adenovirus-infected cells. Following postdoctoral work at the Wistar Institute and the National Cancer Institute, he joined the faculty at the Jefferson Medical College of Thomas Jefferson University. Later, he became the Founder and Director of the Center for Neurovirology and Neurooncology at MCP Hahnemann University School of Medicine in Philadelphia, PA. Dr. Khalili is a Professor and the Founding Chair of the Department of Neuroscience and the Director and Founder of the Center for Neurovirology at the Temple University School of Medicine in Philadelphia, PA. His research program focuses on the viral oncology and the molecular biology of neurotropic viruses, with the goal of understanding the molecular basis of virus-induced or associated neurodegenerative diseases and cancers of the central nervous system.

Eugene O. Major received the Ph.D. degree from the University of Illinois Medical Center in infectious diseases and microbiology and was a part of a team that established a research center there on the genetics of viruses that cause cancer. Following academic appointments as Associate Professor at the University of Illinois Medical School and the Loyola University Medical School in Chicago, where he was also Associate Dean of Graduate Programs, Dr. Major joined the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) in 1981. He has developed a world-recognized translational research laboratory in the Intramural Program focusing on mechanisms of viral pathogenesis in the human nervous system, which includes JC virus-induced demyelination, progressive multifocal leukoencephalopathy, and HIV-1/AIDS-associated encephalopathy. Dr. Major's research program has also established a novel human brain-derived progenitor cell population whose lineage can be directed to all major cell types of the brain, similar to embryonic stem cells.

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