Review
Polyomavirus BK

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Summary

Polyomavirus hominis 1, better known as BK virus (BKV), infects up to 90% of the general population. However, significant clinical manifestations are rare and limited to individuals with impaired immune functions. BKV has been associated with diverse entities such as haemorrhagic cystitis, ureteric stenosis, vasculopathy, pneumonitis, encephalitis, retinitis, and even multi–organ failure. In addition, BKV has been implicated in autoimmune disease and possibly cancer. Due to high prevalence and frequent reactivation, the role of BKV in some of these pathologies has been difficult to define. Development of BKV diseases is likely to require complementing determinants in the host, the target organ, and possibly the virus, that are subject to modulators such as immunosuppression. These complex aspects are highlighted in Polyomavirus associated nephropathy (PAN), an emerging disease in renal allograft recipients that may jeopardise the progress in renal transplantation accomplished in the past 10 years. Intervention is difficult due to the lack of specific antivirals and relies mostly on improving immune control. Diagnostic strategies using urine cytology and BKV load measurements in plasma have led to earlier diagnosis of PAN, which increased the success rate of intervention. Case series suggest that cidofovir might be effective, especially when combined with reduced immunosuppression.

Section snippets

BKV virology

BKV, JCV, and the simian virus SV40 are species of the genus polyomavirus within the polyomaviridae, a family of unenveloped DNA viruses with icosahedral capsids of 45 μm diameter (figure 1). The capsids contain the viral genomes, circular double-stranded DNA of 5300 base pairs (bp) coated by host-cell histones. The BKV genome shares an overall homology of 75% with JCV and of 70% with SV40, and can be divided into regulatory, early, and late region. After virion uptake by endocytosis of

BKV infection, replication, and disease

High prevalence and symptomless reactivation have impeded a clear appreciation of the pathogenic role of BKV. For the purpose of this review, BKV infection, replication, and disease were defined as shown in the panel.

BKV epidemiology

Serological studies indicate that primary BKV infection occurs independently of JCV during childhood at a median age of 4–5 years.14, 15 The seroprevalence is lowest at the age of 6 months after the loss of maternal antibodies and increases to about 75% among adults worldwide (range 46–94%) except for some remote populations in South America and Asia.15 After primary infection, BKV persists in the renourinary tract as the principal site.16 Thus, viraemic spread from the site of entry has to be

BKV transmission

The natural route of transmission has not been established. Serological association of primary infection with upper respiratory infection suggests transmission via aerosol or fomites.22, 23 Urinary shedding argues for oral transmission by contaminated food, water, or smear infection.24 Archetypical strains have been detected in sewage and shellfish samples around the world.25, 26 Transplacental transmission has been proposed based on the detection of IgM in cord blood samples and of BKV DNA by

BKV immunity and reactivation

The innate and adaptive immune response to BKV is little investigated. The JCV—independent increase of BKV seroprevalence during childhood provides evidence for high specificity.14 The humoral immune response consists of IgG, IgM, and IgA, which includes neutralising and subtypespecific antibodies directed against determinants on the BKV major capsid protein VP1.15 The presence of LT—agspecific antibodies indicates that not only virions, but also remnants of infected cells are processed by

Patterns of polyomavirus disease

The pathogenetic role of BKV infection may differ depending on the clinical setting. In a simplistic approach, polyomavirus disease could be divided into different patterns.

Determinants and modulators of BKV disease

BKV disease is likely to depend on multiple, partly complementing risk factors (figure 2).54 Host determinants include BKV serostatus, quality and quantity of immune effectors, and age. Organ determinants include permissiveness for BKV replication, immunological, or toxic injury. Potential viral determinants are serological and replicative characteristics. These determinants and their interaction are affected by rather dynamic dose–dependent and magnitude–dependent modulators such as

Manifestations in immunocompetent individuals

Conceptually, BKV replication in an immunocompetent individual would be most likely to cause disease when the immune effectors are naive as during primary infection. Primary BKV infection is poorly characterised, presumably because of its subclinical or unspecific “flu-like” course. Serological evidence implicated primary BKV infection in 1–20% of children with upper-respiratory-tract symptoms, fever, or malaise.22, 23 BKV genome sequences have been detected by hybridisation in tonsillar tissue

Manifestations in inherited immune dysfunction

Inherited immune dysfunction increases the susceptibility to various infectious complications.60 In two cases, renal failure due to PAN was documented. 42, 43 A 6—year-old boy with hyper-IgM-syndrome (HIM) presented with irreversible renal failure and shedding of decoy cells.42 Renal biopsy showed the by now classic features of PAN (stage B) with multifocal sites of BKV replication and unspecific inflammatory infiltrates. On autopsy 4 months later, progression to diffuse interstitial fibrosis

Manifestations in acquired immune dysfunction

HIV-1 infection represents the most frequent cause of acquired immunodeficiency today. The natural course is characterised by a progressive decline of CD4–cells and lifethreatening opportunistic complications. The major polyomavirus disease in AIDS is JCV-mediated PML affecting 1–6% of patients. Clinical manifestations of BKV in AIDS patients are rare despite frequent reactivation. The prevalence of BKV shedding increases from 4–8% to 27–51% when CD4 cell counts fall below 200/μL, without

Manifestations in therapeutic immune dysfunction

In organ transplantation, suppression of immune responses is indicated to avoid immunological injury and allograft loss. Manifestations of BKV disease may vary according to the transplantation procedures and the corresponding determinants and modulators.

Autoimmune disease and cancer

BKV-specific diagnostic criteria are difficult to establish for malignant transformation or autoimmune disease. BKV may be an innocent bystander, or an initiating lesion that is no longer required for subsequent progression steps (“hit and run”), or may actually support disease activity. BKV infection has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) as one of several potential triggers of an autoimmune response.11 One of the diagnostic hallmarks of SLE activity is

Conclusion

Development of BKV disease is likely to require complementing determinants in the host, the target organ, and possibly the virus, which are subject to dynamic modulators. These complex aspects are highlighted in PAN, an emerging disease in renal allograft recipients. Despite considerable progress in the past 2 years, present understanding of BKV disease is incomplete and needs further research to ultimately improve patient care. A better definition of risk factors and more effective and less

Search strategy and selection criteria

Medline was searched for papers in the English language using the terms “BKV”, “BK virus”, “polyomavirus”, and “polyoma”. For specific sections, search terms were combined with “immunodeficiency”, “HIV”, and “transplantation”. Abstracts of the most recent meetings were reviewed such as the American Transplant Congress, the American Society of Nephrology Congress, and the Interscience Conference on Antimicrobial Agents and Chemotherapy. Articles were selected according to the documented or

References (156)

  • YN Kang et al.

    BK virus infection in renal allograft recipients

    Transplant Proc

    (2003)
  • H Maiza et al.

    Graft dysfunction and polyomavirus infection in renal allograft recipients

    Transplant Proc

    (2002)
  • CK Buehrig et al.

    Influence of surveillance renal allograft biopsy on diagnosis and prognosis of polyomavirus-associated nephropathy

    Kidney Int

    (2003)
  • M Fernandez-Cobo et al.

    Strains of JC virus in Amerind-speakers of North America (Salish) and South America (Guarani), Na-Dene-speakers of New Mexico (Navajo), and modern Japanese suggest links through an ancestral Asian population

    Am J Phys Anthropol

    (2002)
  • GL Stoner et al.

    The human polyomaviruses: past, present and future

  • JA Fishman

    BK virus nephropathy—polyomavirus adding insult to injury

    N Engl J Med

    (2002)
  • Drachenberg CB, Papadimitriou JC, Wali R, Cubitt CL, Ramos E, BK polyoma virus allograft nephropathy: Ultrastructural...
  • I Binet et al.

    Polyomavirus disease under new immunosuppressive drugs: a cause of renal graft dysfunction and graft loss

    Transplantation

    (1999)
  • PS Randhawa et al.

    Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy

    Transplantation

    (2002)
  • R Rubinstein et al.

    Structure and function of the transcriptional control region of nonpassaged BK virus

    J Virol

    (1987)
  • U Moens et al.

    Molecular biology of BK virus and clinical and basic aspectes of BK virus renal infection

  • L Jin et al.

    Genomic typing of BK virus in clinical specimens by direct sequencing of polymerase chain reaction products

    J Med Virol

    (1993)
  • L Jin et al.

    BK virus antigenic variants: sequence analysis within the capsid VP1 epitope

    J Med Virol

    (1993)
  • KV Shah et al.

    High prevalence of antibodies to BK virus, an SV40-related papovavirus, in residents of Maryland

    J Infect Dis

    (1973)
  • WA Knowles

    The epidemiology of BK Virus and the occurrence of antigenic and genomic subtypes

  • PM Chesters et al.

    Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues

    J Infect Dis

    (1983)
  • A Zambrano et al.

    Detection of human polyomaviruses and papillomaviruses in prostatic tissue reveals the prostate as a habitat for multiple viral infections

    Prostate

    (2002)
  • A Sundsfjord et al.

    BK and JC viruses in patients with systemic lupus erythematosus: prevalent and persistent BK viruria, sequence stability of the viral regulatory regions, and nondetectable viremia

    J Infect Dis

    (1999)
  • PD Ling et al.

    The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study

    J Infect Dis

    (2003)
  • A Dolei et al.

    Polyomavirus persistence in lymphocytes: prevalence in lymphocytes from blood donors and healthy personnel of a blood transfusion centre

    J Gen Virol

    (2000)
  • K Dorries

    Latent and persistent polyomavirus infection

  • J Goudsmit et al.

    The role of BK virus in acute respiratory tract disease and the presence of BKV DNA in tonsils

    J Med Virol

    (1982)
  • DW Brown et al.

    BK virus specific IgM responses in cord sera, young children and healthy adults detected by RIA

    Arch Virol

    (1984)
  • A Sundsfjord et al.

    Detection of BK virus DNA in nasopharyngeal aspirates from children with respiratory infections but not in saliva from immunodeficient and immunocompetent adult patients

    J Clin Microbiol

    (1994)
  • S Bofill-Mas et al.

    Documenting the epidemiologic patterns of polyomaviruses in human populations by studying their presence in urban sewage

    Appl Environ Microbiol

    (2000)
  • S Bofill-Mas et al.

    Potential transmission of human polyomaviruses through the gastrointestinal tract after exposure to virions or viral DNA

    J Virol

    (2001)
  • V Pietropaolo et al.

    Transplacental transmission of human polyomavirus BK

    J Med Virol

    (1998)
  • CA Andrews et al.

    A serological investigation of BK virus and JC virus infections in recipients of renal allografts

    J Infect Dis

    (1988)
  • KV Shah

    Human polyomavirus BKV and renal disease

    Nephrol Dial Transplant

    (2000)
  • A Corallini et al.

    Antibodies to BK virus structural and tumor antigens in human sera from normal persons and from patients with various diseases, including neoplasia

    Infect Immun

    (1976)
  • JE Drummond et al.

    Cell-mediated immune responses to BK virus in normal individuals

    J Med Virol

    (1985)
  • JE Drummond et al.

    BK virus specific humoral and cell mediated immunity in allogeneic bone marrow transplant (BMT) recipients

    J Med Virol

    (1987)
  • AV Kahan et al.

    Activation of human polyomavirus infection-detection by cytologic technics

    Am J Clin Pathol

    (1980)
  • TF Hogan et al.

    Survey of human polyomavirus (JCV, BKV) infections in 139 patients with lung cancer, breast cancer, melanoma, or lymphoma

    Prog Clin Biol Res

    (1983)
  • A Sundsfjord et al.

    BK and JC viruses in human immunodeficiency virus type 1-infected persons: prevalence, excretion, viremia, and viral regulatory regions

    J Infect Dis

    (1994)
  • SD Gardner et al.

    Prospective study of the human polyomaviruses BK and JC and cytomegalovirus in renal transplant recipients

    J Clin Pathol

    (1984)
  • RB Markowitz et al.

    Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects

    J Infect Dis

    (1993)
  • WA Knowles et al.

    Prevalence of long-term BK and JC excretion in HIV-infected adults and lack of correlation with serological markers

    J Med Virol

    (1999)
  • IJ Koralnik et al.

    Association of prolonged survival in HLA-A2+progressive multifocal leukoencephalopathy patients with a CTL response specific for a commonly recognized JC virus epitope

    J Immunol

    (2002)
  • EP Richardson et al.

    Atypical progressive multifocal leukoencephalopathy with plasma-cell infiltrates

    Acta Neuropathol Suppl (Berl)

    (1975)
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