JC Virus and BK Virus

BK virus (BKV) and JC virus (JCV) are small, nonenveloped, single-stranded DNA viruses belonging to the Polyomaviridae family, which are ubiquitous in the human population. While the primary infection is usually asymptomatic, the infection leads to lifelong latency in the kidneys and lymphoid organs. Latent infections can become active in immunosuppressed patients. Reactivation of BKV is most often seen in transplant patients and can lead to nephropathy, allograft loss, hemorrhagic cystitis, and urethral stenosis. Reactivation of JCV causes progressive multifocal leukoencephalopathy (PML), which is considered an AIDS-defining condition. Diagnosis can be confirmed with PCR or tissue biopsy. Specific therapy is not available. Management aims to reduce immunosuppression.

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Classification

DNA virus classification flowchart

Identification of DNA viruses:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. Viruses with a DNA genome can be further characterized as single or double stranded. “Enveloped” viruses are covered by a thin coat of cell membrane, which is usually taken from the host cell. If the coat is absent, however, the viruses are called “naked” viruses. Some enveloped viruses translate DNA into RNA before incorporating into the genome of the host cell.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

Taxonomy

  • Family: Polyomaviridae
  • Genus: Betapolyomavirus
  • Species: 
    • Human polyomavirus 1: BK virus (BKV)
    • Human polyomavirus 2: JC virus (JCV)

General features

BKV and JCV share similar characteristics:

  • DNA viruses:
    • Circular
    • Double stranded
  • Structure:
    • Small
    • Nonenveloped
    • Icosahedral
Electron micrograph showing BK virus jc virus and bk virus

Electron micrograph showing BK virus (BKV) virions:
Notice the small size and icosahedral symmetry.

Image: “Viral inclusions seen on electron microscopy of urine epithelial cells” by Perram J et al. License: CC BY 3.0

Associated diseases

  • BKV:
    • BKV-associated nephropathy
    • Ureteral stenosis
    • Hemorrhagic cystitis
  • JCV: progressive multifocal leukoencephalopathy (PML)

Epidemiology

  • Much of the epidemiology of BKV and JCV in the general population is unknown:
    • Source of infectious virus
    • Mode of transmission 
  • Seroprevalence in the United States and Europe: 30%–90%
  • Asymptomatic viruria is detectable in 10%–30% of healthy individuals.
  • Clinical manifestations are rare.

Pathogenesis

Reservoir

Humans are the natural host for JCV and BKV.

Transmission

  • The methods of transmission are poorly understood for both BKV and JVC.
  • Possible routes:
    • Oral
    • Respiratory
    • Perinatal
    • Donor tissue

Host risk factors

The clinical disease most often arises from reactivation of the virus in immunocompromised patients:

  • HIV/AIDS (PML is considered an AIDS-defining condition)
  • Organ transplantation
  • Hematopoietic cell transplantation (HCT)
  • Hematologic malignancies

Pathophysiology

  • The primary infection leads to a subclinical, lifelong persistence in host tissue.
  • Once inside the cell, the virus travels to the nucleus and establishes a latent or lytic infection.
  • Infection is controlled by antibodies and cytotoxic T cells.
  • Failure of the immune response → reactivation
    • JCV:
      • Establishes latency (mainly in the kidneys and lymphoid tissue)
      • Reactivation → replication and production of neurotropic variants
      • Can cross the blood-brain barrier → lytic replication in oligodendrocytes → demyelination → PML
    • BKV:
      • Latency in kidneys
      • Reactivation → ↑ replication → damage to renal tubular and uroepithelial cells and inflammatory infiltration
      • Interstitial inflammation → fibrosis and tubular injury

Clinical Presentation

BKV

Primary infection:

  • Most patients are asymptomatic.
  • Others may have a mild respiratory illness.

Secondary infection:

  • Occurs in immunosuppressed patients
  • BKV-associated nephropathy (more common in renal-transplant patients):
    • Acute kidney injury
    • Hematuria, pyuria, and cell casts
    • Can result in kidney-allograft dysfunction or loss
  • Ureteral stenosis:
    • Urinary tract obstruction
    • Acute kidney injury
  • Hemorrhagic cystitis (more common in HCT recipients):
    • Dysuria
    • Urgency
    • Lower abdominal pain
    • Hematuria
    • Acute kidney injury (secondary to obstruction)

JCV

PML is a progressive (and often fatal) condition most commonly seen in patients with AIDS with a CD4 count < 200 cells/µL.

  • Clumsiness
  • Hemiparesis (most common finding)
  • Aphasia and dysarthria
  • Hemianopia or diplopia
  • Gait ataxia
  • Cognitive impairment
  • Impaired vigilance
  • Headache
  • Seizures (rare)

Diagnosis and Management

Diagnosis

BKV:

  • Plasma-quantitative PCR for BKV DNA:
    • Preferred screening test
    • Perform in all renal transplant patients.
  • Urine cytology for identification of infected cells
  • Renal allograft biopsy:
    • The gold standard for diagnosis
    • Immunohistochemistry can be used to detect BKV antigens.
    • Findings:
      • Intranuclear, basophilic viral inclusions
      • Variation in size of cell nuclei or hyperchromasia (indicates nuclear injury)
      • Tubular injury with interstitial, inflammatory cell infiltrates
      • Tubulitis (lymphocytes in the tubular basement membrane)

JCV:

  • CT or MRI of the brain:
    • Disseminated, nonenhancing, white-matter lesions (indicates demyelination)
    • Do not conform to cerebrovascular territories
    • No mass effect
  • Lumbar puncture with CSF analysis: PCR for JCV DNA (preferred)
  • Brain biopsy:
    • Considered if PCR is negative but suspicion remains high
    • Findings:
      • Demyelination
      • Abnormal astrocytes
      • Enlarged oligodendroglial nuclei
      • Usually, no inflammatory infiltrates
MRI images multifocal leukoencephalopathy

Magnetic resonance imaging (MRI) of a patient with progressive multifocal leukoencephalopathy (PML):
a: axial T2-flair MRI of the brain showing bilateral signal hyperintensity in the parietooccipital white matter
b: axial T2-flair diffuse-weighted image of the same lesions

Image: “Axial T2-Flair MRI and axial T2-Flair diffuse-weighted image” by Jeyaraman VA et al. License: CC BY 2.0

Management

No specific therapies are available for BKV or JCV. Management is generally aimed at reducing immunosuppression.

  • Reduce immunosuppressive therapy (when possible)
  • Antiretroviral therapy for HIV/AIDS 
  • Supportive care

Differential Diagnosis

  • CNS lymphoma: a malignancy associated with Epstein-Barr infection, which can occur in patients with AIDS with a CD4 count < 50 cells/µL. Patients may have headaches, confusion, focal neurologic deficits, seizures, and constitutional symptoms. Brain imaging, CSF studies for cytology and PCR, and brain biopsy can provide the diagnosis. Management includes antiretroviral therapy and chemotherapy.
  • HIV-associated dementia: a condition in patients with AIDS with a CD4 count < 200 cells/µL. Patients present with memory loss, poor executive functioning, behavior and mood changes, and gradual loss of motor skills. MRI may show diffuse, patchy, white-matter hyperintensities. Analysis of CSF should rule out other causes, such as PML and lymphoma. Management includes antiretroviral therapy and supportive measures.
  • Multiple sclerosis (MS): a chronic, inflammatory autoimmune disease leading to demyelination of the CNS. The clinical presentation may include neurological symptoms, which affect vision, motor functions, sensation, and autonomic function. Presentation varies depending on the site of the lesions. Diagnosis is made with MRI imaging of the brain and spine, as well as CSF examination. Management involves corticosteroids for acute exacerbations and disease-modifying agents to slow the progression of the disease.
  • Cytomegalovirus: a ubiquitous, double-stranded DNA virus belonging to the Herpesviridae family. The initial infection is usually asymptomatic in the immunocompetent host. However, reactivation can occur in immunosuppressed patients, causing a host of manifestations such as colitis, hepatitis, pneumonitis, meningoencephalitis, and nephritis. Diagnosis can be confirmed with PCR or biopsy. Management includes antivirals and a decrease in immunosuppressive therapy.

References

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