Journal of Infection (2014) 68, S2eS8

www.elsevierhealth.com/journals/jinf

BK and JC virus: A review

Michelle Pinto, Simon Dobson*

Division of Infectious and Immunological Diseases, Department of Pediatrics, BC Children’s Hospital,

Vancouver, Canada

Accepted 20 September 2013

Available online 8 October 2013

KEYWORDS Summary Polyomaviruses are ubiquitous, species-specific viruses belonging to the family Pa-
Polyomavirus; povaviridae. The two most commonly known human polyomaviruses, BK virus and JC virus were
BK Virus; first described in the 1970s. Newer human polyomaviruses, namely KI polyoma virus, WU poly-
JC Virus oma virus and Merkel cell polyoma virus were identified in the last five years. Most humans
encounter BK and JC virus during childhood, causing mild illness. However, when reactivated
or acquired in the immunocompromised host, BK and JC virus have been implicated in a num-
ber of human clinical disease states. BK is most commonly associated with renal involvement,
such as ureteral stenosis, hemorrhagic cystitis and nephropathy. Less commonly, it is associ-
ated with pneumonitis, retinitis, liver disease and meningoencephalitis. JC virus is most well
known for its association with progressive multifocal leukoencephalopathy, and is possibly
implicated in the development of various human neoplasms. The following chapter will outline
the basic virology, epidemiology and clinical manifestations of BK and JC virus and discuss rele-
vant diagnostic and treatment options.
ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Introduction sample of a renal transplant patient with ureteral stenosis

with the initials “B.K.”5 JC virus was isolated that same
year from a patient with initials “J.C.” who had a history
Human polyomaviruses are a subgroup of polyomaviruses
of Hodgkin’s lymphoma and progressive multifocal leukoen-
belonging to the family Papovaviridae. The first polyoma-
cephalopathy (PML).6 Since then, four more human polyo-
virus was described in 19521 and identified as murine K vi-
maviruses have been identified. In 2007 KI polyoma virus
rus, which was found to cause tumors such as
and WU polyoma virus were isolated from respiratory sam-
adenocarcinoma and leukemia when injected into mice.2
ples of affected patients.7,8 In 2008, Merkel cell polyoma vi-
Polyomaviruses are ubiquitous, and multiple species-
rus was identified and linked to the development of Merkel
specific viruses exist, infecting humans, monkeys, mice,
cell carcinoma in humans3 and, in 2010, trichodysplasia spi-
cattle, rabbits and birds.3,4 In 1971, the virus that later
nulosa virus was described.9
came to be known as BK virus, was isolated from a urine

* Corresponding author.
E-mail addresses: michelle.pinto@cw.bc.ca (M. Pinto), sdobson@cw.bc.ca (S. Dobson).

0163-4453/$36 ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jinf.2013.09.009
BK and JC virus
Virology
Polyomaviruses are non-enveloped, small (w45 nm) viruses
with a circular double-stranded DNA genome.10 This
genome consists of approximately 5000 base pairs
comprising 88% protein and 12% DNA.11 The virus is arranged
in 72 viral capsomeres with icosahedral symmetry. The pol-
yoma viral genome contains three main regions: an early,
non-coding and late region. The early region encodes for
the large tumor antigen (T antigen), which has a role in
infection and the small tumor antigen (t antigen). This early
region is transcribed prior to DNA replication. The non-
coding control region (NCCR) is adjacent to the early region
and contains transcription factors for early and late genes.
The late region is transcribed after DNA replication has
occurred and encodes for viral capsid proteins VP1, VP2,
VP3 and agnoprotein.12
The human polyomaviruses share some homology with
other polyoma viruses and have between 69 and 75% DNA
homology with simian polyomavirus SV40, which may be
capable of causing human disease.13 BK virus has approxi-
mately 75% genome homology with JC virus and 70% homol-
ogy with SV40. The other human polyomaviruses share
similar homology to both BK and JC virus with Merkel cell
polyoma virus having more homology with the African green
monkey lymphotropic virus.3
The life cycle of BK and JC virus involve viral binding to
specific receptors to gain entry into the host cell. In BK
virus, this receptor is an N-linked glycoprotein.14e16 In JC
virus, an alpha (2, 6) sialic acid is involved.17 After binding
to these viral-specific receptors, cell entry is facilitated via
endocytosis.18 Once the virus has gained entry into the host
cell it travels to the endoplasmic reticulum and the VP1
protein facilitates entry into the host cell nucleus, where
viral assembly occurs. The final viral products are released
via host cell lysis.12 Both BK and JC virus can be transmitted
via various routes including: fecal-oral, respiratory,19,20
through blood transfusions, organ transplantation, trans-
placentally and through seminal fluid.21,22 After primary
infection, both BK and JC virus enter a latent phase. For
BK virus, the most common site for latency is the renal
tubular epithelial cells. Latent JC virus can be detected
in a variety of human tissues. It is present in the tonsilar tis-
sues of 39% of healthy individuals.10 Other sites of JC virus
latency include renal tubular cells, bone marrow and
brain.23
Epidemiology
Primary infection with both BK and JC virus typically occur
in childhood, with 50% of children having seroconversion
for BK virus by 3e4 years of age, and for JC virus by 10e15
years of age.24,25 Primary infection is usually asymptom-
atic or associated with mild upper respiratory symptoms.
By adulthood, 80% of people have been infected by either
BK virus, JC virus, or both.26 Asymptomatic viruria is seen
in both healthy and immunocompromised patients,27 and
an approximate of 3% of pregnant patients shed JC or BK
virus in their urine.12 When BK or JC virus infects a host
beyond the age and circumstances of the typical primary
infection, it is usually in the setting of reactivation of
S3
latent infection in an immunocompromised host, whether
it be in relation to immunosuppressive therapy or individ-
ual immunodeficiency. The pathogenesis of viral reactiva-
tion involves a complex interaction between host
predisposition to reactivation, target organ damage and
host immune function.10 Post renal or bone marrow trans-
plantation, the required immunosuppressive therapy can
lead to reactivation of BK virus in host renal cells. Risk
factors for reactivation include: BK virus seropositivity,
older age, and high pre-transplant anti-BK virus IgG.28
The prevalence of BK virus associated nephropathy is be-
tween 1 and 10% in renal transplant patients29,30 with
average diagnosis made by 44 weeks post transplant.31
BK virus related ureteral stenosis occurs in approximately
3% of renal transplant recipients32 versus 0.5e6% in the
overall renal transplant population.33 Hemorrhagic cystitis
occurs in approximately 10e25% of bone marrow trans-
plant patients, and is considered one of the most com-
mons BK-virus related adverse sequelae.34
JC virus is most commonly associated with progressive
multifocal leukoencephalopathy (PML) in immunosup-
pressed patients, including those with hematologic malig-
nancies receiving immunosuppressive therapy35 and up to
5% of patients with AIDS.36 In PML patients, coexisting im-
mune conditions include: AIDS (80%), hematological malig-
nancies (13%), solid organ/bone marrow transplant
recipients (5%) and chronic inflammatory disease (2%).37
Clinical disease
BK virus
BK virus is known to be associated with a variety of
complications in immunocompromised hosts, including:
hemorrhagic cystitis and BK virus associated nephropathy
(BKVAN), and less commonly: pneumonitis, retinitis, liver
disease and meningoencephalitis.10
BK virus associated nephropathy includes both hemor-
rhagic and non-hemorrhagic cystitis, asymptomatic hema-
turia, ureteral stenosis and interstitial nephritis.10 In BK
virus associated nephropathy, reactivation of latent virus
is believed to start soon after renal transplantation, and
is observed in 30e50% of renal transplant recipients within
the first three months after transplantation.38,39 The ne-
phropathy is usually preceded by virus presence in the
urine and plasma.10 Presentation varies, from no symp-
toms, to elevated serum creatinine, fever or hematu-
ria.40,41 Approximately 80% of renal transplant recipients
have BK viruria, and 5e10% of those go on to develop
BKVAN.38,42,43 Reactivation of BK virus in the renal tubular
epithelial cells of these patients occurs irrespective of
type of immunosuppressive therapy,10 and is believed to
be more closely associated with the degree of overall
immunosuppression as opposed to specific medications.44
Of patients that develop BKVAN, approximately 50e80%
go on to develop graft failure, depending on the severity
of inflammation, destruction of renal tubular cells and
renal fibrosis.45
In hemorrhagic cystitis there is little difference between
allogenic and autologous BMT patients with respect to BK
viruria.46 There is an increased incidence of BK hemorrhagic
S4
cystitis in allogenic BMT patients with graft-versus-host dis-
ease which is likely related to an immune reconstitution
etiology.47 Symptoms of hemorrhagic cystitis include hema-
turia, urinary symptoms of dysuria, urgency and frequency
and suprapubic pain. Blood clots can deposit in the urinary
tract leading to urinary obstruction and renal failure.10
Pulmonary manifestations of BK disease include mild
upper respiratory tract infection symptoms in primary
infections in children, but can also include interstitial
pneumonitis and pulmonary fibrosis.48 Ophthamological
complications of BK viral reactivation have been described
in an AIDS patient with bilateral atypical retinitis.49 BK virus
related hepatic disease can be related to transient de-
rangements in liver enzymes that can be noted during pe-
riods of BK viruria.50 Neurologic complications of BK virus
infection have been described in the literature, most
commonly meningoencephalitis in immunocompromised
hosts. In these patients, BK virus was isolated from brain
tissue samples, in addition to other sites such as the kidneys
and lungs in conjunction with correlating clinical disease in
these organs.51e53
JC virus
Progressive multifocal leukoencephalopathy (PML) is a dis-
ease process that occurs in immunocompromised hosts in
relation to JC virus infection. It involves progressive
demyelination of white matter with symptoms of cognitive
deterioration, gait and coordination abnormalities, limb
paresis and seizure activity.54 Prognosis is generally poor,
with improved outcomes associated with strong cellular im-
mune response.55 Neuroimaging studies including CT and
MRI can help in the diagnosis of PML by helping to visualize
white matter lesions in the absence of mass effect or
contrast enhancement.10 CT findings are typically consis-
tent with hypodense lesions, while MRI shows hyperinten-
sity on T2-weighted and FLAIR images, with hypointense
lesions on T1-weighted views. MRI is considered more sensi-
tive than CT for diagnosis of PML.56
While the association between polyomaviruses and
neoplasms is established, JC virus specifically has been
implicated in the pathogenesis of colorectal cancer.57 The
theory of oncongenesis of JC virus in the colon and rectum
relates to the ability of a cell to be permissive or non-
permissive in response to viral DNA replication. In oligo-
dendrocytes, this replication is permitted, leading to lysis
of infected cells. However, colorectal epithelial cells lack
this permissiveness, which can lead to undetected infec-
tion with resultant malignant cell transformation.58 While
JC virus DNA can be detected in various neoplastic lesions
including gliomas, ependymomas, medulloblastomas and
gastrointestinal tumors,59 a direct causation between
viral infection and malignancy in these tissues is difficult
to prove. The large T antigen of JC virus has been impli-
cated in promoting gene damage in colorectal tissues,
which may contribute to neoplastic conversion.60,61 Evi-
dence is emerging showing that JC virus large T antigen
DNA was present in 28e30% of colorectal carcinomas,
while other JC virus protein was only found in 16% of these
same lesions. Furthermore, the detection of large T anti-
gen DNA was less frequent in benign colorectal adenomas
M. Pinto, S. Dobson
and absent in the normal tissue surrounding the malignant
lesions.62
Diagnosis
BK virus
BK virus can be isolated in the urine of both symptomatic
and asymptomatic patients via urine PCR. Urine viral load is
generally 1000-fold higher than in the plasma.63 The diag-
nosis of BKVAN is usually accepted if BK viruria exists in
conjunction with renal insufficiency.10 Decoy cells are vir-
ally infected epithelial cells with enlarged and abnormal
nuclei and irregular shape that can sometimes mimic
neoplastic cells. The presence of urinary decoy cells is
believed to be indicative of BK virus infection, although
they are also present in JC virus and adenovirus infec-
tions.64,65 While BK virus urine PCR can be useful in diag-
nosing BKVAN, its utility is less in diagnosing BK virus
related hemorrhagic cystitis, as many patients can have
asymptomatic viruria without disease. Positive urine tests
should be confirmed with plasma viral PCR and renal biopsy
if possible. In these cases following the trend in BK viruria
can also be useful as elevations in urinary viral load may
be associated with progression in clinical disease.10
Conversely, if urinary BK virus PCR is negative it is more
sensitive for excluding BK virus as a cause of disease. Renal
biopsy can help detect viral replication in renal tubular
epithelial cells via visualization of intranuclear inclusions
and cell detachment.66 However, due to the focality of BK
virus in renal tissue false negatives can be observed and
may occur in up to 30% of cases.10 Plasma viral PCR is
more useful if negative, as it has a negative predictive
value of 100% for BKVAN but a positive predictive value of
only 50%.67 Of more utility, is observing the quantitative
measurement of BK viral load in the plasma. Elevated
plasma viral load in excess of 104 copies/mL has both 93%
specificity and sensitivity for associated positive tissue his-
tology of BKVAN.68 In hemorrhagic cystitis and ureteral ste-
nosis, plasma viral PCR may be of limited value as viral load
is usually undetectectable in these forms of BK virus
disease.10
JC virus
As previously discussed, neuroimaging may be useful in the
diagnosis of JC virus related PML. In PML, brain biopsy is
considered to be the gold standard for diagnosis, with a
sensitivity of 64e96% and a specificity of 100%.10 Histologi-
cally, evidence of demyelination and gliosis is present with
abnormal astrocytes and macrophages.69 Due to the diffi-
culty and risk involved in obtaining brain tissue, CSF anal-
ysis for JC virus is often used as a surrogate test. CSF
profile in JC virus infection shows non-specific changes
with increased white blood cell count, mildly elevated pro-
tein and normal glucose. The sensitivity for detection of JC
virus in CSF via PCR is 72e92% with a specificity of
92e100%.70 These values were accurate prior to the intro-
duction of highly active anti-retroviral therapy (HAART)
for HIV-affected patients. In patients who are now on
BK and JC virus
HAART, the sensitivity of JC virus PCR in CSF decreases to
58%.71
Treatment
BK virus
The mainstay of treatment for BK virus nephropathy is to
decrease the immunosuppression, as there is currently no
specific anti-viral for BK virus. Clearance of BK viremia can
be indicative of nephropathy resolution.10 A prospective
study done in 2007 by Ginervi et al.72 of BKV surveillance
in pediatric renal transplant patients indicated that BK viru-
ria was present in 63% of patients, with a median onset at 3
months post transplant. BK viremia was present in 21% of
patients. A decrease in immunosuppression resulted in a
clearance of viremia in those patients, and prevented ne-
phropathy without an associated increase in the graft
dysfunction or rejection rate. Another prospective study
in the pediatric population showed that a 50% reduction
in immunosuppressive therapy resulted in clearing BK
viremia in 58% of patients with presumed nephropathy.73
The treatment for ureteral stenosis is similar, with decrease
in immunosuppression in conjunction with surgical manage-
ment of associated obstruction.10
BK virus related hemorrhagic cystitis is mainly symptom-
atic, employing hyperhydration, induced increased urine
output via diuretics, bladder irrigation and pain manage-
ment and maintenance of platelet count greater than
50,000.10
In conjunction with decreased immunosuppression,
other pharmaceutical treatment modalities include Cido-
fovir, Leflunomide, quinolones and intravenous immuno-
globulin (IVIG). Cidofovir is a viral DNA polymerase inhibitor
that has been approved for treatment of AIDS-related CMV
retinitis. While it has not been formally approved for
treatment of polyomavirus associated nephropathy,
in vitro action against murine polyoma virus has been
demonstrated.
Investigational use of Cidofovir at low doses (0.25e1 mg/
kg IV biweekly) was used as treatment for refractory BK
nephropathy in a review of two renal transplant patients by
Kadambi et al. in 2003.74 In this study clearance of BK virus
from blood and allograft was observed with stabilization of
renal function in both patients. It should be noted however,
that cidofovir is renally excreted, and risks of nephrotoxi-
city and further renal insufficiency should be weighed
against treatment benefits. Another study by Vats et al.75
in four patients with nephropathy indicated that cidofovir
treatment resulted in clearance of BK viruria in all patients,
although it recurred in half of them. No persistent nephro-
toxicity was noted in these patients.
Leflunomide is pyrimidine synthesis inhibitor that has
both immunosuppressive and antiviral properties, and has
been approved for the treatment of rheumatoid arthritis.
The mechanism of action in BK viral infection is Lefluno-
mide’s inhibition of mitochondrial enzymes involved in
producing metabolites required for cell cycle progression.
This inhibition prevents expansion of activated lympho-
cytes. Williams et al. studied 17 patients with biopsy-
proven BK nephropathy.76 In conjunction with decreased
S5
immunosuppresion, the patients were treated with Lefluno-
mide to target blood levels between 50 and 100 mcg/mL.
Fifteen of the seventeen patients had viral clearance or
decrease in viremia.
Quinolones are antibacterial drugs that are DNA gyrase
inhibitors. The proposed mechanism of action in BK virus
treatment is interference with large T antigen helicase
activity for BK virus both in vivo and in vitro.77e79 A study
by Chandraker et al. indicated that a ten-day course of ga-
tifloxacin resulted in a decrease in BK viremia or urinary
decoy cells two months after treatment.80 Support for using
IVIG is mixed, with potential effects on BK viremia but no
significant improvement in graft survival.81,82
JC virus
As with BK virus, there is no specific antiviral therapy for JC
virus. The main goal of therapy in PML is to optimize HAART.
If this can be achieved, one-year survival of HIV positive
PML patients increases from 10 to 50%.83 In HIV-negative pa-
tients, as with BK virus, reduction in immunosuppression is
the goal of therapy.10 Cytarabine, a chemotherapy agent
that interferes with DNA synthesis, has been explored as
a potential treatment modality, as in vitro studies have
shown an effect on JC virus replication.55 The studies
have shown mixed results as far as cytarabine efficacy,
however one study demonstrated stabilization of PML in
37% of HIV-negative test subjects with lymphoma or leuke-
mia.84 Mirtazapine, a serotonin receptor blocker is being
studied as a potential treatment for JCV due to the role
of serotonin receptors in JC virus infection.85
In summary, BK and JC viruses are ubiquitous human
polyomaviruses with varied clinical presentation. Primary
infection in childhood is usually associated with mild
clinical illness, but the impact of these polyomavirus
infections in immunosuppressed patients remains a signif-
icant concern. Additionally, BK and JC virus have been
implicated in oncogenesis in human hosts, warranting
ongoing study of this phenomenon.
Conflict of interest
None
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