JC virus

JC virus (JCPyV) is a small non-enveloped DNA virus carried silently for life by most of the adult population and notorious for one devastating consequence: progressive multifocal leukoencephalopathy (PML), a subacute demyelinating disease of the central nervous system (the brain and spinal cord). The virus infects the great majority of people in childhood without symptoms and then persists indefinitely in the kidney and lymphoid tissue. It causes disease only when cellular immunity collapses, when it reaches the brain and replicates unchecked in oligodendrocytes, the cells that make myelin. PML was a rarity until the HIV pandemic made it the commonest cause of viral brain disease in advanced immunosuppression, and it has since become the feared complication of several potent immunomodulatory drugs, above all natalizumab in multiple sclerosis. There is no antiviral that clears JC virus; the only effective treatment is to restore the immune control that normally keeps it silent, which makes early recognition and the prevention of iatrogenic disease the heart of management. Its close relative BK virus shares the same persistence in the urinary tract but causes disease in the transplanted kidney and bladder rather than the brain.

Discovery and historical significance

PML was defined as a clinical and pathological entity in 1958, in patients immunosuppressed by chronic lymphocytic leukaemia and Hodgkin lymphoma, as a rare fatal demyelinating disease with a peculiar histology: patches of myelin loss studded with enlarged oligodendrocyte nuclei and grotesque reactive astrocytes. A viral cause was suspected when electron microscopy in 1965 revealed polyomavirus-like particles packed into the abnormal oligodendrocyte nuclei.

The virus itself was isolated in 1971, when Padgett and colleagues recovered a previously unknown human polyomavirus by inoculating brain tissue from a PML patient onto primary cultures of human fetal glial cells. The isolate was named JC after that patient, John Cunningham. In the same year a second human polyomavirus, BK virus, was recovered from the urine of a renal transplant recipient, and the two have been studied as a pair ever since. For four decades JC and BK were the only polyomaviruses unequivocally linked to human disease. JC virus held mainly academic interest until the 1980s, when the AIDS epidemic multiplied the number of profoundly immunosuppressed people and turned PML from a curiosity into a common and dreaded diagnosis. A second transformation came in 2005, when PML appeared in patients with multiple sclerosis and inflammatory bowel disease treated with natalizumab, establishing JC virus as the defining hazard of an entire class of immunomodulatory therapies.

Classification, structure, and genome

Classification

JC virus is a member of the family Polyomaviridae, genus Betapolyomavirus, with the current International Committee on Taxonomy of Viruses species name Betapolyomavirus secuhominis (formerly Human polyomavirus 2). The family was separated from the old Papovaviridae once sequencing showed that polyomaviruses transcribe their genome bidirectionally from a central control region, unlike the unidirectional papillomaviruses. Its closest medically important relatives are the other human betapolyomaviruses, BK virus (Betapolyomavirus hominis) and the simian virus SV40, while the oncogenic Merkel cell polyomavirus sits in the genus Alphapolyomavirus. More than a dozen human polyomaviruses are now recognised, most of them without a proven disease association.

Virion structure

The virion is a non-enveloped icosahedral particle about 40 to 45 nanometres in diameter (some sources give 45 to 50). Its capsid follows the polyomavirus plan of 72 pentamers arranged on a triangulation number T equals 7 lattice: 360 molecules of the major capsid protein VP1 form the 72 pentamers, and each pentamer carries a single molecule of either VP2 or VP3 tucked inside, so only VP1 is exposed on the surface and presents the receptor-binding site. The capsid is held together by calcium ions and by disulfide bonds between pentamers, which is why chelating agents under reducing conditions dissociate it into VP1 pentamers. Being non-enveloped, the particle is stable and resists heat, lipid solvents and formalin. The genome travels inside as a minichromosome, wound on the host histones H2A, H2B, H3 and H4.

Genome organisation

The genome is a single circular molecule of double-stranded DNA of about 5,000 base pairs, organised into three functional parts. The early region, transcribed before DNA replication, encodes the large T antigen and the small t antigen by alternative splicing of a single messenger RNA. The late region, transcribed in the opposite direction after replication begins, encodes the three capsid proteins VP1, VP2 and VP3 together with the small regulatory agnoprotein. Between the two lies the non-coding control region (NCCR), which holds the single origin of replication and a bidirectional promoter and enhancer driving transcription both ways.

The NCCR is the key to JC virus pathology. The form found in the urine and kidney of healthy carriers, called the archetype, has a simple linear arrangement of promoter elements. Disease-associated virus from brain and blood carries a rearranged NCCR, with deletions and duplications of those elements (the prototype, or Mad-1, configuration). The rearranged forms replicate more efficiently and shift the balance towards lytic infection of glial cells, so the architecture of this short non-coding stretch, rather than any change in the proteins, marks the switch from harmless persistence to neurovirulence.

Replication cycle

JC virus follows the canonical polyomavirus replication arc, with one decisive departure that defines its clinical behaviour: it does not establish true herpesvirus-style latency but persists as a chronic, low-level infection that reactivates only when immune control is lost.

Attachment is to the linear sialylated pentasaccharide lactoseries tetrasaccharide c on the cell surface, with entry depending on a co-receptor, the serotonin 5-HT2A receptor, which is expressed on glial cells and helps explain the virus’s tropism for the brain. This serotonin-receptor dependence is the rationale for trialling serotonin antagonists such as mirtazapine against PML. The virus enters by receptor-mediated endocytosis through clathrin-coated pits and is trafficked along microtubules not to the lysosome but to the endoplasmic reticulum. There the rigid capsid is partially disassembled by the cell’s protein disulfide-isomerase machinery, because the intact particle is too large to cross the nuclear pore. The partly uncoated genome, carried by nuclear localisation signals on its capsid proteins, then enters the nucleus.

Inside the nucleus the genome is transcribed by host RNA polymerase II. Large T antigen is the master replication protein: it binds the origin as a double hexamer, unwinds the DNA with its helicase activity, and recruits the host replication apparatus (replication protein A, DNA polymerase alpha-primase and topoisomerase) that the virus does not encode. To make those factors available, large T antigen forces resting cells into S phase by binding and inactivating the retinoblastoma family of tumour suppressors through its LXCXE motif, and it also binds p53; small t antigen reinforces this by dysregulating the cellular phosphatase PP2A. Once viral DNA replication is under way, the late genes are transcribed, the capsid proteins assemble new particles in the nucleus, and progeny virions are released by lysis of the permissive cell.

The persistence that follows primary infection is not a silent, gene-free latency but a chronic productive infection at low level in the kidney and lymphoid tissue, held in check by T-cell immunity. Reactivation, rearrangement of the control region and spread to the brain, probably carried by infected B-lineage cells, occur together only when that immunity fails.

Pathogenesis

PML is the prototype of a directly cytopathic viral disease of the brain. When immune control lapses, JC virus reaches the central nervous system and replicates lytically in oligodendrocytes. Because each oligodendrocyte myelinates many axons, their destruction produces expanding, coalescing areas of demyelination in the subcortical white matter, while the axons themselves are relatively spared until late. The histological signature is a triad: enlarged oligodendrocyte nuclei with ground-glass inclusions packed with virions at the edge of lesions, bizarre multinucleated reactive astrocytes that can mimic tumour cells, and lipid-laden foamy macrophages clearing the myelin debris, all with surprisingly little inflammatory infiltrate in the classical untreated case.

Almost all PML patients are already JCPyV-seropositive, so the disease represents reactivation of long-standing infection rather than a newly acquired one. The failure of cellular immunity is central: PML in HIV is concentrated in patients with very low CD4 counts, and recovery of JCPyV-specific CD8 cytotoxic T cells predicts survival. Beyond the classic white-matter disease, JC virus can infect other neural cells: lytic infection of cerebellar granule cell neurons causes a distinct cerebellar syndrome, and infection of cortical pyramidal neurons produces an encephalopathy, both reflecting the virus’s capacity to adapt its tropism.

Two molecular changes appear to license neurovirulence. The first is the rearrangement of the non-coding control region, which raises replication in glial cells and is found in brain and blood but not in the archetype shed from the kidney. The second is mutation of the VP1 receptor-binding pocket: variants that lose binding to the sialylated glycan and rely on the serotonin 5-HT2A receptor are enriched in central nervous system disease, a shift that may favour spread among glial cells over release into the urine. How the virus reaches the brain is not fully resolved, but infected B lymphocytes and their precursors are thought to carry it across the blood-brain barrier, which fits both the lymphoid persistence of the virus and the particular risk posed by drugs, like natalizumab, that disturb lymphocyte trafficking. The brain disease is therefore the product of a permissive host, a rearranged and receptor-shifted virus, and a route of delivery that all converge only when immune surveillance is gone.

When immunity is restored too abruptly, the returning T-cell response can overshoot and attack JCPyV-infected cells, producing an immune reconstitution inflammatory syndrome (IRIS). This adds inflammation, oedema and contrast enhancement to the lesions and can worsen the clinical picture even as the infection is being controlled, a paradox that is most familiar after starting antiretroviral therapy and after removing natalizumab by plasma exchange.

Epidemiology

JC virus is distributed worldwide, and the majority of adults are seropositive. Seroprevalence climbs through life, from a minority of young children to roughly half to three-quarters of older adults, indicating that primary infection is common, lifelong and asymptomatic. The route of transmission is not firmly established; the virus is found in tonsillar tissue, in urine and in sewage, which points to a respiratory or faecal-oral acquisition in childhood. JC virus genotypes track the migrations of human populations so closely that they have been used as a marker of ancestral movement, evidence of how stably the virus is transmitted within families and communities over generations.

Disease, by contrast, is confined to the profoundly immunosuppressed. Before effective antiretroviral therapy, PML affected a few per cent of people with AIDS, which accounted for the great majority of cases. The other major risk groups are patients with multiple sclerosis treated with natalizumab, recipients of solid organ and haematopoietic stem cell transplants, people with haematological malignancies such as chronic lymphocytic leukaemia and lymphoma, those treated with other lymphocyte-depleting or trafficking-blocking agents, and the rare patients with idiopathic CD4 lymphopenia.

Natural history

The natural history is a long quiescence punctuated, in a few unlucky hosts, by catastrophe. Primary infection in childhood is silent. The virus then persists for life in the kidney and lymphoid tissue, shed intermittently in the urine of many healthy people without any consequence. In the immunocompetent host this balance is never disturbed. Only when cellular immunity is durably impaired does the virus rearrange its control region, reactivate and disseminate to the brain. From the point at which immune control fails to the appearance of neurological disease the interval varies with the depth and cause of immunosuppression: it can be months in advanced HIV, while in natalizumab-treated patients the risk rises with cumulative duration of therapy, climbing markedly after about two years of treatment. Untreated, PML is relentlessly progressive and usually fatal within months; its course is altered only by restoring immune function.

Clinical presentations and complications

The dominant presentation is PML itself. It begins insidiously and progresses over weeks to months, with focal deficits that reflect the location of the white-matter lesions rather than any single syndrome: limb weakness, visual field loss including homonymous hemianopia, cognitive and behavioural change, speech and language disturbance, incoordination and gait ataxia. Headache and fever are characteristically absent, and seizures occur mainly when lesions reach the cortex or when inflammation supervenes. The deficits accumulate as the lesions expand and coalesce.

The phenotype differs somewhat by setting. In advanced HIV, PML often presents late, with established multifocal deficits and large confluent lesions. In natalizumab-treated patients it is increasingly caught early, while deficits are still mild or even before symptoms, because these patients are under active imaging surveillance; their lesions tend to be more inflammatory and more often enhance with contrast, and frontal and parietal involvement with cognitive and behavioural change is common. Prognosis tracks the speed and degree of immune recovery. Untreated PML is almost uniformly fatal within months. With effective antiretroviral therapy, around half of patients with HIV-associated PML now survive, though many are left with permanent neurological disability, and natalizumab-associated PML, especially when detected presymptomatically, has a better survival still, at the price of a near-universal inflammatory reconstitution syndrome.

JC virus also causes several less common neurological syndromes, distinguished by the cell type infected:

Syndrome	Cell infected	Clinical picture
Progressive multifocal leukoencephalopathy	Oligodendrocytes (white matter)	Subacute multifocal deficits; demyelination
JC granule cell neuronopathy	Cerebellar granule cell neurons	Progressive cerebellar ataxia
JCPyV encephalopathy	Cortical pyramidal neurons	Cognitive decline; grey-matter disease
JCPyV meningitis	Meninges (rare)	Headache and meningism; spinal fluid JCPyV DNA

A further complication is PML-IRIS, the inflammatory worsening that follows immune recovery. It can either unmask previously subclinical disease or aggravate established lesions, and in the natalizumab setting it is almost universal after plasma exchange. Severe IRIS with cerebral oedema and raised intracranial pressure is itself life-threatening and may require corticosteroids to control. Outside the nervous system JC virus is a rare cause of a polyomavirus nephropathy, with high urinary viral loads but, unlike BK virus, little or no detectable virus in the blood.

Diagnosis

The diagnosis of PML rests on the combination of a compatible clinical picture, characteristic imaging and detection of JCPyV DNA in the cerebrospinal fluid. Magnetic resonance imaging is central: it shows one or more areas of subcortical white matter that are hyperintense on T2-weighted and on FLAIR (fluid-attenuated inversion recovery, the sequence that suppresses normal fluid signal so that diseased or damaged white matter stands out clearly) sequences and hypointense on T1, without mass effect and classically without contrast enhancement, although enhancement does appear when there is inflammation or IRIS, which is commoner in the natalizumab and post-transplant settings than in untreated HIV.

JCPyV DNA in the spinal fluid, detected by polymerase chain reaction, is the key confirmatory test, and a positive result in the right clinical and radiological context is taken as laboratory-confirmed PML. An important caveat is sensitivity: the assay misses roughly a quarter of histologically proven cases, particularly when the viral load is low or when antiretroviral therapy has already reduced it, so a negative spinal fluid result does not exclude the disease. Where doubt remains, the options are to repeat the test, to measure an intrathecal anti-JCPyV antibody response, or to proceed to stereotactic brain biopsy, which remains the definitive test: it shows the histological triad together with viral protein on immunohistochemistry or viral genome by in situ hybridisation. Diagnostic certainty is graded as possible, probable or laboratory-confirmed according to which of these elements are present.

Routine cerebrospinal fluid examination is usually unremarkable, with normal or only mildly raised protein and a normal cell count, which helps separate PML from the infective meningoencephalitides that produce a brisk pleocytosis. The main differential is the rest of the immunosuppressed brain: in HIV that means HIV encephalitis, cerebral toxoplasmosis, primary central nervous system lymphoma and cytomegalovirus encephalitis, distinguished on imaging by PML’s lack of mass effect and (untreated) lack of enhancement, and by the relevant microbiological and molecular tests. The temporal pattern matters too, since the same patient starting antiretroviral therapy may develop PML-IRIS, and telling genuine progression from inflammatory reconstitution can require serial imaging rather than a single scan.

A separate diagnostic role belongs to the JCPyV antibody index, a standardised measure of anti-JCPyV serum antibody used not to diagnose PML but to stratify the risk of developing it before and during natalizumab therapy. A seronegative patient is at low risk, while a high antibody index, conventionally above about 1.5, marks substantially higher risk and is one of the inputs to the risk calculation described below.

Management

There is no antiviral drug that clears JC virus, and the single principle of treatment is to restore JCPyV-specific cellular immunity as quickly as is safe. In HIV-associated PML this means starting or optimising combination antiretroviral therapy (cART) to suppress HIV and allow CD4 recovery; survival improved markedly once effective antiretroviral therapy became available, although surviving patients are often left with neurological deficits. In drug-associated PML the priority is to withdraw the responsible agent. For natalizumab, because the antibody has a long duration of action, its removal is accelerated by plasma exchange or immunoadsorption, which clears the drug and restores normal lymphocyte trafficking into the central nervous system, at the cost of a near inevitable IRIS that then has to be managed in its own right. In transplantation and other iatrogenic settings, immunosuppression is reduced as far as the graft or underlying condition allows.

Many specific therapies have been tried and none has proven efficacy in controlled study, so they are mentioned only as the reality of a disease without a licensed treatment. Agents directed at the virus or its receptor have included cidofovir and its derivative brincidofovir, the serotonin antagonist mirtazapine, mefloquine and cytarabine, all without demonstrated benefit. More recent approaches aim to boost the immune response rather than the virus: the immune-checkpoint inhibitor pembrolizumab, which blocks PD-1 to reinvigorate exhausted T cells, has stabilised or improved some patients in small case series, and adoptive transfer of JCPyV-specific or cross-reactive BK-virus-specific T cells is under investigation. Corticosteroids have no role against the infection itself and are reserved for severe inflammatory IRIS with raised intracranial pressure, used briefly rather than long term.

Prevention and public health

Because disease arises from reactivation of a near-universal childhood infection, there is no prospect of preventing JC virus acquisition, and prevention instead means avoiding iatrogenic PML through the rational use and active monitoring of immunomodulatory therapy. The model is natalizumab, an antibody against the alpha-4 integrin used for highly active relapsing-remitting multiple sclerosis (RRMS), which blocks lymphocyte entry into the brain and so removes the immune surveillance that contains JC virus. Its PML risk is stratified by three factors: JCPyV serostatus and antibody index, prior use of immunosuppressant drugs, and duration of natalizumab treatment.

Risk factor	Lower risk	Higher risk
JCPyV antibody index	Seronegative or low index	Index above about 1.5
Prior immunosuppressant use	None	Previous immunosuppression
Duration of therapy	Under about two years	Beyond about two years

Seronegative patients carry a low risk and are retested periodically, since seroconversion on therapy raises their risk. Seropositive patients with a high antibody index, prior immunosuppression and prolonged treatment occupy the highest-risk group, with a PML incidence on the order of several to more than ten per thousand. For them, risk is managed by more frequent magnetic resonance surveillance, every few months rather than annually, to detect early presymptomatic lesions, and by discontinuing natalizumab at the first radiological or clinical sign of PML, because outcomes are far better when the disease is caught before it becomes symptomatic. The same logic of weighing immunosuppressive benefit against PML risk, and of vigilance for new neurological signs, applies to the other agents associated with the disease.

Vaccination

There is no vaccine against JC virus and none is in prospect. A vaccine would face the difficulty that almost everyone is already infected, so the target would be not to prevent acquisition but to boost the cellular immunity that controls reactivation, in precisely the patients whose immune systems are least able to respond. The practical preventive levers therefore remain immune restoration and the careful stewardship of immunomodulatory drugs rather than immunisation.

South African context

JC virus has no dedicated South African surveillance programme, and PML is not a notifiable condition, but its epidemiology in the country is dominated by the scale of the HIV epidemic. In a population with one of the world’s largest numbers of people living with HIV, HIV-associated PML is the principal form of the disease, concentrated in patients presenting late with advanced immunosuppression or failing antiretroviral therapy, and the cornerstone of both prevention and treatment is early HIV diagnosis with prompt, sustained antiretroviral therapy to prevent the profound CD4 depletion in which PML occurs. Diagnosis depends on access to magnetic resonance imaging and to JCPyV polymerase chain reaction testing, which are concentrated in tertiary and academic centres, so a clinical and radiological suspicion of PML in an immunosuppressed patient often has to be referred for confirmation. Natalizumab-associated PML, by contrast, is uncommon, because the drug is expensive and not widely used in the South African setting.

References and recommended reading

• DeCaprio JA, Imperiale MJ, Hirsch HH. Polyomaviridae. In: Howley PM, Knipe DM, Damania BA, Cohen JI, eds. Fields Virology: DNA Viruses. 7th ed. Wolters Kluwer; 2022:1-44. The primary reference for the molecular virology, the replication cycle, persistence, and the JCPyV- and BKPyV-associated diseases.
• Greenlee JE, Hirsch HH. Polyomaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. ASM Press; 2016. The clinical account of PML, its variants, diagnosis and management.
• Fenner and White’s Medical Virology, 5th edition. Academic Press; 2017, Chapter 20 (Polyomaviruses). Concise overview of the family and the human polyomaviruses.