Questions

JC virus — Questions

Study questions about JC virus — exam-style, clinical-scenario and FAQ.

Mock Exam mode

Sit this set one question at a time. Multiple-choice questions mark themselves; written questions reveal a tickable mark scheme so you can score your own answer. You get a combined score at the end.

11 questions: 6 MCQ, 5 written.

High-priority (past-paper) questions only

Why C

JC virus attaches to a sialylated glycan and depends on the serotonin 5-HT2A receptor, expressed on glial cells, to enter; this helps explain its tropism for the brain and underlies the trial of serotonin antagonists such as mirtazapine. CD4 is the HIV receptor, the nicotinic acetylcholine receptor is used by rabies virus, CR2 by Epstein-Barr virus, and the epidermal growth factor receptor by other viruses.

Why D

There is no specific antiviral for the JC virus. The only effective intervention is antiretroviral therapy, which restores CD4 immunity and lets the patient regain control of the virus; immune reconstitution is the principal determinant of survival, and antiretroviral therapy should not be delayed.

Ganciclovir, aciclovir and cidofovir have no useful activity against JC virus. Corticosteroids are used only to dampen a severe immune-reconstitution reaction (PML-IRIS), not as primary treatment, and the outlook remains poor even with antiretroviral therapy.

Natalizumab blocks lymphocyte entry into the brain, removing the immune surveillance that contains JC virus, so PML is its defining hazard.

Risk stratification

Three factors set the risk. The serum JC virus antibody index: seronegative patients are at low risk, while a high index (conventionally above about 1.5) marks substantially higher risk. Prior use of immunosuppressant drugs raises risk further. So does duration of treatment, with risk climbing markedly beyond about two years. A patient who is seropositive with a high index, has had previous immunosuppression and has been treated for several years sits in the highest-risk group.

Monitoring

Seronegative patients are retested periodically, because seroconversion on therapy raises their risk. Higher-risk patients undergo more frequent magnetic resonance surveillance, every few months rather than annually, to detect early or presymptomatic lesions, since outcome is far better when PML is caught before it becomes symptomatic.

Management if PML develops

Stop natalizumab and accelerate its clearance with plasma exchange or immunoadsorption to restore normal lymphocyte trafficking. There is no specific antiviral. Restoring immune surveillance almost inevitably provokes an immune reconstitution inflammatory syndrome, which is then managed in its own right, with corticosteroids reserved for severe inflammation with raised intracranial pressure.

PML is a directly cytopathic disease that emerges only when cellular immunity fails.

Reactivation under immunosuppression

Most adults carry JC virus as a lifelong, low-level persistent infection of the kidney and lymphoid tissue, controlled by T-cell immunity. PML is reactivation of this infection, not a new one: almost all patients are already seropositive, and disease appears only with profound immunosuppression, classically advanced HIV with a low CD4 count or treatment with agents such as natalizumab. Loss of JC-virus-specific CD8 cytotoxic T cells is the decisive failure.

Reaching and damaging the brain

Two molecular changes license neurovirulence: rearrangement of the non-coding control region from the urinary archetype to the disease-associated prototype, which raises replication in glial cells, and mutation of the VP1 receptor-binding site favouring the serotonin 5-HT2A receptor on glia. Infected B-lineage cells are thought to carry the virus across the blood-brain barrier. There it replicates lytically in oligodendrocytes, the myelin-producing cells. Because each oligodendrocyte myelinates many axons, their destruction produces expanding, coalescing demyelination of the subcortical white matter, with the histological triad of enlarged oligodendrocyte nuclei, bizarre reactive astrocytes and foamy macrophages, and little inflammation until immune reconstitution supervenes.

A complete answer links each laboratory test to the clinical and radiological picture, since the diagnosis is made on the combination rather than on any single result.

Cerebrospinal fluid JC virus PCR

The central test is detection of JC virus DNA in cerebrospinal fluid by polymerase chain reaction. In a patient with compatible neurology and characteristic imaging, a positive result confirms the diagnosis (laboratory-confirmed PML) and removes the need for brain biopsy. Detection in the cerebrospinal fluid is meaningful because the virus is not normally present there, unlike urine and blood, where asymptomatic shedding is common. Quantification is useful for monitoring. The key limitation is sensitivity: the assay misses roughly a quarter of histologically proven cases, particularly at low viral load or after antiretroviral therapy has reduced it, so a negative result does not exclude PML. Routine cerebrospinal fluid is usually otherwise normal, which helps separate PML from the meningoencephalitides that produce a pleocytosis.

When the PCR is non-informative

Where the result is negative but suspicion persists, the options are to repeat the test, to measure an intrathecal anti-JC virus antibody response, or to proceed to stereotactic brain biopsy. Biopsy remains the definitive test, showing the histological triad of demyelination, enlarged oligodendrocyte nuclei and bizarre astrocytes, with confirmation by viral protein on immunohistochemistry or viral genome by in situ hybridisation.

Putting it together

The laboratory does not diagnose PML in isolation: it supplies the virological confirmation that, set against the clinical syndrome and the magnetic resonance imaging appearance, allows the case to be graded as possible, probable or laboratory-confirmed. The serum JC virus antibody index has no role in diagnosing an established case; it is a risk-stratification tool in the natalizumab setting.

The result is meaningful precisely because the site is privileged.

A positive result signifies central nervous system disease

JC virus is not normally present in cerebrospinal fluid, unlike urine and blood, where most healthy adults shed or harbour the virus without consequence. Detection of JC virus DNA in the cerebrospinal fluid therefore indicates replication within the central nervous system rather than incidental persistence. In a patient with a compatible clinical picture and characteristic magnetic resonance imaging, a positive PCR confirms the diagnosis as laboratory-confirmed PML and removes the need for brain biopsy. Viral load can be quantified to support monitoring.

Interpret with the clinical and radiological context

The result is read together with the syndrome and the imaging, not alone. A positive PCR without compatible clinical or radiological features should prompt review rather than an immediate diagnosis. The converse caveat also matters: because the assay misses about a quarter of proven cases, a negative result does not exclude PML, so the positive result is the more decisive of the two.

Why B

Cerebrospinal fluid JC virus PCR misses roughly a quarter of histologically proven cases, especially at low viral load, so a negative result does not exclude PML when the clinical and radiological picture is typical. The appropriate next steps are to repeat the PCR, consider an intrathecal antibody index, or proceed to brain biopsy, not to abandon the diagnosis.

Why D

There is no specific antiviral for JC virus; the single effective principle is to restore JC-virus-specific immunity, which in HIV means starting or optimising antiretroviral therapy. Aciclovir has no activity against polyomaviruses, cidofovir has not shown benefit, corticosteroids are reserved only for severe immune reconstitution inflammation, and mirtazapine is unproven and not a treatment in its own right.

Clinical and radiological features

PML presents subacutely over weeks with focal deficits that reflect lesion location rather than a single syndrome: limb weakness, visual field loss, cognitive or behavioural change, speech disturbance and ataxia. Fever and headache are characteristically absent. Magnetic resonance imaging shows one or more areas of subcortical white matter that are hyperintense on T2-weighted and FLAIR sequences and hypointense on T1, without mass effect and, in the untreated HIV setting, usually without contrast enhancement.

Differential diagnosis

The differential is the rest of the advanced-HIV brain. HIV encephalitis causes a more diffuse, symmetrical leukoencephalopathy with cognitive decline. Cerebral toxoplasmosis and primary central nervous system lymphoma both produce mass lesions with oedema and ring or homogeneous enhancement, unlike PML. Cytomegalovirus encephalitis tends to be periventricular. The lack of mass effect and enhancement, the multifocal white-matter pattern, and a positive cerebrospinal fluid JC virus PCR distinguish PML, with biopsy reserved for unresolved cases.

Why A

JC virus is a polyomavirus: a small non-enveloped icosahedral particle with a circular double-stranded DNA genome of about 5 kilobases, whose large T antigen drives the cell into S phase to support replication. Option C describes a parvovirus, B a picornavirus or similar, E an orthomyxovirus, and D an enveloped DNA virus such as a herpesvirus.

Why E

Restoring immunity can provoke an immune reconstitution inflammatory syndrome, in which the returning T-cell response attacks JC-virus-infected cells; the formerly non-enhancing PML lesions develop enhancement and oedema and the patient worsens even as infection is being controlled. The timing after antiretroviral therapy and the new enhancement point to PML-IRIS rather than drug toxicity, simple progression, abscess or haemorrhage.

High priorityMCQ
JC virus enters glial cells using which molecule as co-receptor?
- A. The CD4 glycoprotein
- B. The nicotinic acetylcholine receptor
- C. The serotonin 5-HT2A receptor
- D. The complement receptor CR2
- E. The epidermal growth factor receptor
Show answer
Correct answer: C
Why C

JC virus attaches to a sialylated glycan and depends on the serotonin 5-HT2A receptor, expressed on glial cells, to enter; this helps explain its tropism for the brain and underlies the trial of serotonin antagonists such as mirtazapine. CD4 is the HIV receptor, the nicotinic acetylcholine receptor is used by rabies virus, CR2 by Epstein-Barr virus, and the epidermal growth factor receptor by other viruses.
High priorityMCQ
What is the most effective treatment for progressive multifocal leukoencephalopathy in a patient with AIDS?
- A. Intravenous ganciclovir
- B. High-dose aciclovir
- C. Cidofovir
- D. Antiretroviral therapy
- E. Corticosteroids alone
Show answer
Correct answer: D
Why D

There is no specific antiviral for the JC virus. The only effective intervention is antiretroviral therapy, which restores CD4 immunity and lets the patient regain control of the virus; immune reconstitution is the principal determinant of survival, and antiretroviral therapy should not be delayed.

Ganciclovir, aciclovir and cidofovir have no useful activity against JC virus. Corticosteroids are used only to dampen a severe immune-reconstitution reaction (PML-IRIS), not as primary treatment, and the outlook remains poor even with antiretroviral therapy.
High priorityClinical scenarioA patient with highly active relapsing-remitting multiple sclerosis is treated with natalizumab. Outline how the risk of progressive multifocal leukoencephalopathy is stratified, monitored and managed.
Model answer
Natalizumab blocks lymphocyte entry into the brain, removing the immune surveillance that contains JC virus, so PML is its defining hazard.

Risk stratification

Three factors set the risk. The serum JC virus antibody index: seronegative patients are at low risk, while a high index (conventionally above about 1.5) marks substantially higher risk. Prior use of immunosuppressant drugs raises risk further. So does duration of treatment, with risk climbing markedly beyond about two years. A patient who is seropositive with a high index, has had previous immunosuppression and has been treated for several years sits in the highest-risk group.

Monitoring

Seronegative patients are retested periodically, because seroconversion on therapy raises their risk. Higher-risk patients undergo more frequent magnetic resonance surveillance, every few months rather than annually, to detect early or presymptomatic lesions, since outcome is far better when PML is caught before it becomes symptomatic.

Management if PML develops

Stop natalizumab and accelerate its clearance with plasma exchange or immunoadsorption to restore normal lymphocyte trafficking. There is no specific antiviral. Restoring immune surveillance almost inevitably provokes an immune reconstitution inflammatory syndrome, which is then managed in its own right, with corticosteroids reserved for severe inflammation with raised intracranial pressure.
High priorityExam-styleDescribe the pathogenesis of progressive multifocal leukoencephalopathy. [5]
Model answer
PML is a directly cytopathic disease that emerges only when cellular immunity fails.

Reactivation under immunosuppression

Most adults carry JC virus as a lifelong, low-level persistent infection of the kidney and lymphoid tissue, controlled by T-cell immunity. PML is reactivation of this infection, not a new one: almost all patients are already seropositive, and disease appears only with profound immunosuppression, classically advanced HIV with a low CD4 count or treatment with agents such as natalizumab. Loss of JC-virus-specific CD8 cytotoxic T cells is the decisive failure.

Reaching and damaging the brain

Two molecular changes license neurovirulence: rearrangement of the non-coding control region from the urinary archetype to the disease-associated prototype, which raises replication in glial cells, and mutation of the VP1 receptor-binding site favouring the serotonin 5-HT2A receptor on glia. Infected B-lineage cells are thought to carry the virus across the blood-brain barrier. There it replicates lytically in oligodendrocytes, the myelin-producing cells. Because each oligodendrocyte myelinates many axons, their destruction produces expanding, coalescing demyelination of the subcortical white matter, with the histological triad of enlarged oligodendrocyte nuclei, bizarre reactive astrocytes and foamy macrophages, and little inflammation until immune reconstitution supervenes.
High priorityExam-styleDiscuss the role of the virology laboratory in the diagnosis of a case of probable progressive multifocal leukoencephalopathy. [10]
Model answer
A complete answer links each laboratory test to the clinical and radiological picture, since the diagnosis is made on the combination rather than on any single result.

Cerebrospinal fluid JC virus PCR

The central test is detection of JC virus DNA in cerebrospinal fluid by polymerase chain reaction. In a patient with compatible neurology and characteristic imaging, a positive result confirms the diagnosis (laboratory-confirmed PML) and removes the need for brain biopsy. Detection in the cerebrospinal fluid is meaningful because the virus is not normally present there, unlike urine and blood, where asymptomatic shedding is common. Quantification is useful for monitoring. The key limitation is sensitivity: the assay misses roughly a quarter of histologically proven cases, particularly at low viral load or after antiretroviral therapy has reduced it, so a negative result does not exclude PML. Routine cerebrospinal fluid is usually otherwise normal, which helps separate PML from the meningoencephalitides that produce a pleocytosis.

When the PCR is non-informative

Where the result is negative but suspicion persists, the options are to repeat the test, to measure an intrathecal anti-JC virus antibody response, or to proceed to stereotactic brain biopsy. Biopsy remains the definitive test, showing the histological triad of demyelination, enlarged oligodendrocyte nuclei and bizarre astrocytes, with confirmation by viral protein on immunohistochemistry or viral genome by in situ hybridisation.

Putting it together

The laboratory does not diagnose PML in isolation: it supplies the virological confirmation that, set against the clinical syndrome and the magnetic resonance imaging appearance, allows the case to be graded as possible, probable or laboratory-confirmed. The serum JC virus antibody index has no role in diagnosing an established case; it is a risk-stratification tool in the natalizumab setting.
High priorityExam-styleWhat is the significance of a JC virus PCR-positive result on cerebrospinal fluid?
Model answer
The result is meaningful precisely because the site is privileged.

A positive result signifies central nervous system disease

JC virus is not normally present in cerebrospinal fluid, unlike urine and blood, where most healthy adults shed or harbour the virus without consequence. Detection of JC virus DNA in the cerebrospinal fluid therefore indicates replication within the central nervous system rather than incidental persistence. In a patient with a compatible clinical picture and characteristic magnetic resonance imaging, a positive PCR confirms the diagnosis as laboratory-confirmed PML and removes the need for brain biopsy. Viral load can be quantified to support monitoring.

Interpret with the clinical and radiological context

The result is read together with the syndrome and the imaging, not alone. A positive PCR without compatible clinical or radiological features should prompt review rather than an immediate diagnosis. The converse caveat also matters: because the assay misses about a quarter of proven cases, a negative result does not exclude PML, so the positive result is the more decisive of the two.
MCQ
A patient with clinical and MRI features typical of PML has a negative cerebrospinal fluid JC virus PCR. The best interpretation is:
- A. PML is reliably excluded by the negative result
- B. PML is not excluded; the assay misses about a quarter of cases
- C. The white-matter lesions must be artefactual
- D. The diagnosis is instead BK virus encephalitis
- E. No repeat PCR, intrathecal antibody testing or brain biopsy is needed
Show answer
Correct answer: B
Why B

Cerebrospinal fluid JC virus PCR misses roughly a quarter of histologically proven cases, especially at low viral load, so a negative result does not exclude PML when the clinical and radiological picture is typical. The appropriate next steps are to repeat the PCR, consider an intrathecal antibody index, or proceed to brain biopsy, not to abandon the diagnosis.
MCQ
The most effective management of HIV-associated PML is to:
- A. Give high-dose intravenous aciclovir
- B. Administer intrathecal cidofovir with probenecid cover
- C. Start long-term high-dose corticosteroids
- D. Restore immune function with antiretroviral therapy
- E. Treat with oral mirtazapine alone
Show answer
Correct answer: D
Why D

There is no specific antiviral for JC virus; the single effective principle is to restore JC-virus-specific immunity, which in HIV means starting or optimising antiretroviral therapy. Aciclovir has no activity against polyomaviruses, cidofovir has not shown benefit, corticosteroids are reserved only for severe immune reconstitution inflammation, and mirtazapine is unproven and not a treatment in its own right.
Clinical scenarioA patient with HIV and a CD4 count below 100 cells per microlitre develops progressive right-sided weakness and a visual field defect over several weeks. Describe the clinical and radiological features of PML and its main differential diagnoses.
Model answer
Clinical and radiological features

PML presents subacutely over weeks with focal deficits that reflect lesion location rather than a single syndrome: limb weakness, visual field loss, cognitive or behavioural change, speech disturbance and ataxia. Fever and headache are characteristically absent. Magnetic resonance imaging shows one or more areas of subcortical white matter that are hyperintense on T2-weighted and FLAIR sequences and hypointense on T1, without mass effect and, in the untreated HIV setting, usually without contrast enhancement.

Differential diagnosis

The differential is the rest of the advanced-HIV brain. HIV encephalitis causes a more diffuse, symmetrical leukoencephalopathy with cognitive decline. Cerebral toxoplasmosis and primary central nervous system lymphoma both produce mass lesions with oedema and ring or homogeneous enhancement, unlike PML. Cytomegalovirus encephalitis tends to be periventricular. The lack of mass effect and enhancement, the multifocal white-matter pattern, and a positive cerebrospinal fluid JC virus PCR distinguish PML, with biopsy reserved for unresolved cases.
MCQ
JC virus is best described as:
- A. A non-enveloped virus with a circular double-stranded DNA genome
- B. An enveloped virus with a positive-sense single-stranded RNA genome
- C. A non-enveloped virus with a linear single-stranded DNA genome
- D. An enveloped virus with a double-stranded DNA genome
- E. A non-enveloped virus with a segmented RNA genome
Show answer
Correct answer: A
Why A

JC virus is a polyomavirus: a small non-enveloped icosahedral particle with a circular double-stranded DNA genome of about 5 kilobases, whose large T antigen drives the cell into S phase to support replication. Option C describes a parvovirus, B a picornavirus or similar, E an orthomyxovirus, and D an enveloped DNA virus such as a herpesvirus.
MCQ
Two weeks after starting antiretroviral therapy, a patient with PML deteriorates, and new MRI lesions now show contrast enhancement and oedema. The most likely explanation is:
- A. Antiretroviral drug toxicity
- B. Inevitable progression of untreated PML
- C. A new bacterial cerebral abscess
- D. Haemorrhagic transformation of the demyelinating lesions
- E. Immune reconstitution inflammatory syndrome
Show answer
Correct answer: E
Why E

Restoring immunity can provoke an immune reconstitution inflammatory syndrome, in which the returning T-cell response attacks JC-virus-infected cells; the formerly non-enhancing PML lesions develop enhancement and oedema and the patient worsens even as infection is being controlled. The timing after antiretroviral therapy and the new enhancement point to PML-IRIS rather than drug toxicity, simple progression, abscess or haemorrhage.