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REVIEW ARTICLE
BK Virus: A Clinical Review
Mark D. Reploeg,1 Gregory A. Storch,2 and David B. Clifford1
1
Department of Neurology and 2Departments of Pediatrics, Medicine, and Molecular Microbiology,
Washington University School of Medicine, St. Louis
BK virus, a relative of JC virus, which is the etiologic
agent of progressive multifocal leukoencephalopathy
(PML), was first isolated in 1971 from a urine sample
obtained from a renal transplant recipient [1]. The name
of the virus refers to the first patient’s initials, which is
also true of JC virus [2]. This member of the polyoma
subgroup of papovaviruses, which includes BK virus, JC
virus, and simian virus 40 (SV-40) [3], is a ubiquitous
virus with peak seroprevalence in early childhood that
ranges from 60% to 100% [4–9]. Epidemiological studies
were performed in a variety of countries, including England (peak seroprevalence in early childhood, 83%) [7],
Finland (60%) [8], Germany (71%) [10], Italy (83%)
[6], and the United States (69%, 100%) [4, 5]. Differences in percentages can be explained by the age of the
tested subjects and the antibody titer threshold that is
considered to be positive.
Primary infection with this double-stranded DNA
Received 26 July 2000; revised 7 December 2000; electronically published 20
June 2001.
Reprints or correspondence: Dr. Mark D. Reploeg, c/o Dr. David B. Clifford,
Washington University School of Medicine, Neurology, Box 8111, 660 S. Euclid,
Saint Louis, MO 63110 ([email protected]).
Clinical Infectious Diseases 2001; 33:191–202
2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3302-0009$03.00
virus is generally asymptomatic and occurs in childhood. The most common symptoms, when symptoms
are noted, are fever and nonspecific upper respiratory
infection [3, 5, 8, 11]. After primary infection has occurred, the virus can remain latent in many sites
[12–27], most notably the kidney [24] (there is controversy regarding latent infection of other sites [26,
28–32]). Transmission may occur by means of exposure
to bodily fluids, such as oral secretions, or via transplacental passage [10, 17, 18, 33–35]. In states of relative
or absolute cellular immunodeficiency, the virus can
become reactivated and cause disease. Figure 1 illustrates the course of BK viral infection.
The kidney, lung, eye, liver, and brain are sites of BK
virus–associated disease, both primary and reactivated.
BK virus infection in the kidney manifests as hemorrhagic and nonhemorrhagic cystitis [36–46], ureteric
stenosis [1, 47, 48], and nephritis [19, 49–60]. Pulmonary diseases that involve BK virus include pneumonitis [19, 59, 61] and acute nonspecific upper respiratory tract infection [8, 11, 62]. To date, reports
regarding ophthalmologic manifestations are limited to
one description of a patient with bilateral atypical retinitis [63]. Liver involvement has also been reported
only rarely [64]. BK virus has also been detected in the
tissue samples of a variety of neoplasms, which have
predominantly been brain tumors of glial and neural
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We present a review of the clinically oriented literature about BK virus, a relative of JC virus, which is the
etiologic agent of progressive multifocal leukoencephalopathy (PML). The kidney, lung, eye, liver, and brain
have been proposed as sites of BK virus–associated disease, both primary and reactivated. BK virus has also
been detected in tissue specimens from a variety of neoplasms. We believe that BK virus is most often
permissively present in sites of disease in immunosuppressed patients, rather than being an etiologic agent
that causes symptoms or pathologic findings. There is, however, strong evidence for BK virus–associated
hemorrhagic cystitis and nephritis, especially in recipients of solid organ or bone marrow transplants. Now
that BK virus can be identified by use of specific and sensitive techniques, careful evaluation of the clinical
and pathologic presentations of patients with BK virus will allow us to form a clearer picture of viral-associated
pathophysiology in many organ systems.
We selected articles for review on the basis of a complete
search of the Medline database that was conducted in September 2000 and that used the key words “BK virus” and the subject
“Polyomavirus hominis 1.” We selected 577 English-language
articles from the 611 citations. Articles were then screened for
their general applicability to clinical practice. Further citations
were identified from the reference sections of selected individual
articles. By use of this method, a total of 158 papers were
analyzed in detail for review.
BK VIRUS TRANSMISSION
origin [16, 65–70], although there is controversy regrading associations between these neoplasms and BK virus [71–77]. A
few investigators have proposed various mechanisms whereby
BK virus can induce neoplasia [20, 65, 68, 70, 78–87]. Table 1
summarizes the proposed mechanisms of BK virus–induced
neoplasia. There may even be an association between BK virus
and autoimmune disease [90]. Although rarely recognized, BK
virus might cause both primary CNS disease and reactivation
CNS disease as well [19, 49, 91, 92]. Table 2 summarizes the
diseases that have been reported to be associated with BK virus.
Our study is intended as a review of the literature regarding
all reported types of BK virus–associated disease, with some emphasis on neurologic manifestations of BK virus. The development of diagnostic testing has made clinical correlations with BK
infection possible. In this article, we review clinical observations
associated with this virus and we summarize the observations
that have been made to date in this evolving clinical diagnostic
era. Both primary and reactivated disease in various organs, along
with pertinent pathologic findings, diagnosis, and treatment,
where appropriate, will be discussed. It is important to understand the spectrum of disease that may be attributed to BK virus,
because BK virus may cause disease in multiple organ systems,
especially in immunosuppressed patients.
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Figure 1. Proposed life cycle of BK virus as applicable to human
disease. URI, upper respiratory infection; ?, organ systems or disease
processes whose association with BK virus has uncertain support in the
literature.
Many different routes for the transmission of BK virus have
been hypothesized. According to many authors, respiratory
transmission is the most likely route [17, 33]. The supportive
studies are epidemiological in nature, and no laboratory, to our
knowledge, has isolated BK virus on cultures of samples of
respiratory secretions. Sexual transmission has been proposed
as another mechanism [18, 94]. Monini et al. [18] detected BK
virus in 57% of specimens of genital tissues and 95% of sperm
samples. Because primary infection generally occurs before the
age of sexual activity, this hypothesis would assume a sexually
transmitted trigger for reactivation of BK disease [5]. A final
proposed mechanism of transmission is transplacental passage
of BK virus. This mechanism was postulated soon after the
discovery of BK virus [10, 34], although further studies were
unable to demonstrate isolation of BK virus from specimens
of either maternal or fetal tissues [95]. It was not until more
sensitive techniques were developed, such as PCR, that Pietropaolo et al. [35] demonstrated the presence of BK viral DNA
in a high proportion of aborted fetuses and in the products of
normal pregnancies.
Other modes can be considered for BK viral transmission,
including via urine and blood. As is discussed in the BK Latency
section, BK virus can remain latent in the kidney in immunocompetent and immunodeficient patients with viruria with
a range of 0%–60% of patients [96], depending on the assay
that was used in the study [3, 97–99]. In one study, an increase
in prevalence of viruria correlated with a decrease in CD4 cell
count [99]. Although it is unknown whether transmission via
urine may be another means by which BK virus is spread, it
should be noted that BK virus has been isolated in cultures of
urine samples cultured with human embryonic kidney [47] and
lung [1, 100] cell lines. A similar argument can be made regarding the spread of BK virus via exposure to blood, because
BK virus has been demonstrated to be present in peripheral
blood leukocytes by use of in situ DNA hybridization (ISH)
[21]. However, demonstration of the presence of BK virus by
means of cultures of peripheral blood leukocytes, to our knowledge, has not been successfully attempted.
Table 1.
Proposed mechanisms by which BK virus may induce neoplasia.
BK virus substrate
Interaction
Host cell substrate
Mechanism of neoplasia
Reference
BK T Ag
Binding
p53
Blockade of apoptosis
[82]
BK T Ag
Unknown
pRb, p107, p130
Blockade of apoptosis
[82–84]
BK T Ag
Unknown
E2F
Increased cell growth or division
[82, 84]
BK T Ag
Unknown
Host cell DNA
Chromosomal aberrations
[82, 85, 86]
BK T Ag
Unknown
Estrogen receptors
Estrogen-mediated cell growth or division
[88, 89]
BK DNA
Binding
HIV Tat1 protein
Induce expression of BK virus genes
[81]
BK DNA promoter
Rearrangement
BK DNA promoter
Increased BK viral replication
[65, 68, 87]
BK VIRUS LATENCY
BK VIRUS AND RENAL DISEASE
Primary BK virus infection is proposed as the cause of a variety
of renal diseases, including hemorrhagic and nonhemorrhagic
cystitis in immunocompetent and immunocompromised patients [38–40]. There are also 2 case reports of tubulointerstitial
nephritis; one patient had underlying hyperimmunoglobulin M
immunodeficiency [51], and the other patient had cartilage hair
hypoplasia and Hodgkin’s disease [52].
To date, the kidney is the most reported site of BK virus
reactivation. Disease associations range from asymptomatic hematuria to hemorrhagic cystitis in recipients of bone marrow
transplants and renal allograft transplants [36, 37, 41–44, 46].
It should be noted that acute, late-onset, long-duration hemorrhagic cystitis is the type of cystitis that is most often associated with BK virus [45, 46, 100], rather than early-onset transient cystitis, which often is secondary to treatment with
cyclophosphamide [46]. In recipients of renal allograft transplants, BK virus–induced ureteric stenosis [1, 47, 48] and tubulointerstitial nephritis [50, 53–55, 58, 60] may be observed,
as demonstrated by means of ISH [47] and IHC [50, 53–55,
58, 60] techniques, respectively. Hypotheses regarding the association of BK virus with hemorrhagic and nonhemorrhagic
cystitis are supported by seroepidemiologic evidence—that is,
increases in immunoglobulins that are specific for BK viral
proteins and the circumstantial presence of BK viruria at the
time of presentation [36, 37, 41–44, 46]. BK virus–induced
allograft nephropathy may be more common in patients who
are treated with certain immunosuppressive regimens. Some
supportive evidence exists for an association with tacrolimus
[53, 56, 109] and mycophenolate mofetil [57], although prospective data are needed to confirm these findings. Other renal
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Many authors have reported that BK virus can exist in a latent
phase in various organs [12–27]. Much of the data are based
on PCR experiments; exceptions are mentioned below. Similar
in concept to the latent state of the herpesvirus [101], these
authors propose that BK virus can remain within a cell in a
nonreplicating or minimally replicating form. Within the cell,
the latent viral genome may either remain episomal or it may
be integrated in the host cell genome. In either state, few if any
viral genes are transcribed, thereby keeping the virus out of
reach of the immune system. Implicit in the definition of latency is the concept of virus reactivation in certain settings
[101]. Virus reactivation and the variety of primary infections
that are associated with BK virus, according to organ system,
are discussed below.
The kidney is the most common reported site of latent infection [24–26]. This has been demonstrated by means of both
immunohistochemistry (IHC) [102] and ISH [24, 26]. The
second most common reported site of latent infection is the
brain [12, 14–16, 27], although some laboratories have failed
to reproduce these findings [26, 30–32]. Peripheral blood leukocytes are also proposed as a site of latency [16, 21–23]; one
laboratory demonstrated this by means of ISH [21], although
others laboratories have failed to replicate their results [28, 29].
A more recent study has even suggested that BK virus is only
present in the blood during the period of reactivation and not
during latency [103]. There are limited data that suggest the
involvement of other sites and tissues, including the pituitary
gland [13], tonsils and nasopharynx [17], genital tissues and
sperm [18], lung [19], liver [20], and bone [16]. In the sites
of latent BK virus infection, the particular cell types that are
involved include blood leukocytes [21], connective tissue cells,
uroepithelial cells, endothelial cells, ependymal cells in the
brain, and astrocytes [33, 102].
Reactivation disease is observed in patients with relative or
absolute immunodeficiency (generally cellular immunodeficiency rather than humoral immunodeficiency), which is made
evident by the increased frequency of reactivation disease in
HIV-infected patients and patients who have received organ
transplants [3]. States of mild immune impairment can lead
to increased virus replication and the presence of the virus in
urine. This phenomenon occurs, for example, in pregnant
women [92, 104, 105], patients with diabetes [106], and elderly
patients [107]. States of more severe immune compromise, such
as AIDS, lymphoproliferative disease, or immunosuppressive
therapy, occasionally result in rampant virus replication and
damage to the involved organs [33, 108].
Table 2.
Diseases to date that have been associated with BK virus.
a
Site, type of disease
Disease
Reference
CNS
Primary
Reactivation
Encephalitis
[91]
Guillain-Barre´ syndrome
[92]
Meningoencephalitis
[19, 49]
Hemorrhagic or nonhemorrhagic cystitis
[38–40]
Kidney
Primary
Reactivation
Tubulointerstitial nephritis
[51, 52]
Hemorrhagic cystitis or hematuria
[36, 37, 41–44, 46]
Tubulointerstitial nephritis
[19, 49, 50, 53–60]
Ureteric stenosis
[1, 47, 48]
Pulmonary system
URI nonspecific
[8, 11, 17, 62]
Interstitial desquamative pneumonitis
[19, 59, 61]
Atypical retinitis
[63]
Eyes
Reactivation
Liver
Hepatitis (transient)
[64]
Autoimmune system
Systemic lupus erythematosus
[90]
CNS neoplasms
Astrocytoma
[16, 68]
Choroid plexus papilloma
[16]
Ependymoma
[16, 65, 67, 68]
Glioblastoma
[16, 66, 68]
Glioma
[65, 66]
Meningioma
[65, 66, 68]
Neuroblastoma
[16, 65]
Oligodendroglioma
[16, 66, 68]
Spongioblastoma
[16, 68]
Pancreas
Islet cell tumors
[68, 93]
Renal neoplasms
Kidney and urinary tract
[20, 87]
Sarcoma neoplasms
Ewing’s tumor
[65]
Osteogenic
[65]
Bone neoplasms
Reticulum cell
[69]
Giant cell
[16]
a
Causality has not been proven for most of these diseases.
manifestations that have been reported include 5 cases of nephritis in patients with AIDS [19, 49, 50, 58, 59]. Of note, 2
of these 5 patients were also found to have BK virus–associated
neurologic disease [19, 49].
Pathologic lesions in the kidney after BK virus infection have
a characteristic appearance. Macroscopically, investigators report streaky fibrosis of the medulla and circumscribed cortical
scars [19, 49]. Microscopically, one sees sclerosed glomeruli,
atrophic and necrotic tubules, and interstitial fibrosis associated
with a mononuclear cell infiltration [19, 49, 51, 58, 59]. Fibrocytes and tubule cells are often enlarged with intranuclear
inclusions that test positive for BK viral DNA by use of ISH
[19, 52, 102]. Because of this strong histopathologic evidence,
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BK virus can be considered an important cause of disease in
the kidney, especially tubulointerstitial nephritis in patients who
have received transplants [53–55].
Diagnosis of BK virus–induced kidney disease has relied
heavily on biopsy-based evidence because of the nonspecificity
of BK viruria [3, 56, 96–99]. Recently, PCR testing of plasma
samples obtained from recipients of renal allograft transplants,
which used seminested primers, has proven to be a sensitive
(100%) and specific (88%) means to determine BK virus–
associated nephropathy [110], although we recommend performing a renal biopsy to confirm a positive PCR result. This
significant finding may pave the way to a greater understanding
of all BK virus–associated diseases.
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Primary
Reactivation
BK VIRUS AND PULMONARY DISEASE
Some children with acute, nonspecific, upper respiratory tract
infections have primary BK virus infections, as demonstrated by
the finding of serologic studies of an increase in the levels of
IgM specific for BK viral proteins [8, 11, 62]. One article described an 8-month-old child who had fatal BK virus–
associated interstitial pneumonia after the child underwent bone
marrow transplantation [61]. Goudsmit et al. [11] also found
BK viral DNA in the tonsils of children with recurrent attacks
of upper respiratory tract infection, although the researchers
could not recover any infectious virus particles. Another report
demonstrated the presence of BK viral DNA in 2 of 201 nasopharyngeal aspirates specimens obtained from children with
acute, nonspecific, upper respiratory tract infections; however,
once again, no infectious particles were isolated, and the results
of IHC that was specific for BK viral antigens were negative [17].
The inability to isolate the virus from these samples and the
infrequency of aspirates that test positive for BK virus brings
into question issues regarding primary respiratory infection.
Reactivation pulmonary disease in association with BK virus
has been reported twice in the literature. One case report described a patient with AIDS for whom the findings of a pathologic examination, which included results of IHC that were
positive for BK viral antigens, confirmed interstitial desquamative pneumonitis [19]. Of note, this patient also had neurologic symptoms. Another patient with AIDS who had interstitial pneumonitis was recently described; the interstitial
pneumonitis progressed to acute respiratory distress syndrome
and the patient died [59].
Fibrosis, although nonspecific, is the most common finding
in tissues samples obtained from patients who have experienced
BK viral infection and replication. The pathologic findings of
the lung of the patient reported by Vallbracht et al. [19] were
consistent with those of BK viral infection in that the primary
finding was fibrosis. There were intra-alveolar aggregates of
pneumocytes, focal hemorrhages, and areas of focal interstitial
fibrosis associated with a mononuclear cell infiltrate. Pneumocytes, fibrocytes, and occasional endothelial cells were found
to contain BK viral DNA, by means of ISH, and viral antigens,
by means of IHC [19]. The second patient with AIDS had
similar pathologic findings—diffuse alveolar damage and mild
interstitial inflammation [59]. The ISH evidence makes the
association strong, but again, there is no proof of causality.
BK VIRUS AND OPHTHALMOLOGIC DISEASE
Ophthalmologic manifestations are described in only 1 recent
report of a case of reactivation disease that presented as bilateral
atypical retinitis in a patient with AIDS [63]. The patient presented with subacute visual deterioration and other neurologic
symptoms [49]. The lesions that were found during the clinical
examination were consistent with those of multifocal retinitis
and were unlike the lesions that are frequently associated with
cytomegalovirus (CMV) or toxoplasmosis [63].
Pathologic investigation of the eye disclosed several areas of
retinal necrosis of full thickness in the outer portion of the
retina. BK viral DNA was found by use of PCR; CMV DNA
was also revealed in some samples. Further investigation determined CMV to be a contaminant from peripheral blood
cells [63], because BK virus was present, as determined by use
of ISH and IHC, whereas CMV was not. Further studies are
required before BK virus can be considered an important cause
of ophthalmologic disease.
BK VIRUS AND HEPATIC DISEASE
There is a single report in the literature regarding an association
between BK virus and hepatic dysfunction. Transient elevations
of liver enzymes were found in a majority of patients who were
concurrently found to be excreting virus in the urine [64]. There
are no reports of pathologic findings in the liver associated with
BK viral infection, although one study did demonstrate the presence of BK viral DNA in normal liver tissue [20]. To our knowledge, these observations have not been replicated, and we include
them here only for the sake of completeness.
BK VIRUS AND AUTOIMMUNE DISEASE
There is literature that described an association between BK
virus infection and a number of autoimmune disorders—
namely, systemic lupus erythematosus. Many researchers have
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There is a small amount of literature concerning the treatment of patients with BK virus disease in the kidney. For example, surgical intervention to relieve obstruction has been
used to treat patients with ureteric stenosis [60]. Vogeli et al.
[46] reviewed the means of treating bone marrow transplant
recipients with hemorrhagic cystitis associated with BK virus.
When hemorrhagic cystitis is mild, it has been treated with
intravenous hyperhydration with some success. In more severe
cases, such treatments as laser vaporization of papulous tumors
(if present at the site of bleeding) and insertion of suprapubic
catheters, followed by continuous bladder irrigation, have met
with more modest success, although they are only reserved for
life-threatening situations [46]. One recent study of patients
who had interstitial nephritis after they underwent kidney allograft transplantation found that a reduction in the doses of
the drugs used in immunosuppressive therapy is currently the
best therapeutic approach [55]. This therapy is difficult to administer to patients who have undergone transplantation because of the risk of graft rejection.
noted the induction of anti–double-stranded DNA and histone
antibodies caused by primary BK virus infection and reactivation disease [89, 111–115]. This finding in humans has been
replicated experimentally in mouse models [116]. Another
group of researchers reported an increased prevalence and persistence of BK viruria in patients with systemic lupus erythematosus. In their study, the prevalence of BK viruria was 16%
in patients with systemic lupus erythematosus and 0% in controls. Of the 20 patients who were tested, persistent or recurrent
viruria was found in 60% of patients with systemic lupus erythematosus [90]. This same relationship is seen between BK
virus and other autoimmune diseases, including rheumatoid
arthritis and polymyositis [117]. Although whether there is
causality has not been determined, the possibility of an association deserves further consideration and research.
Neoplastic tissue types. The transforming activity of BK virus
has long been known from many authors’ work with human,
transgenic, and other mammalian cell lines [66, 79, 92,
118–121]. Subsequent work has focused on the search for BK
virus DNA in many human neoplasms. In particular, brain
tumors, such as ependymomas, meningiomas, glioblastomas,
gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, and neurinomas, have been
shown to contain BK viral DNA [15, 16, 65–68]. There is some
controversy, however, concerning the presence of BK viral DNA
in glioblastoma multiforme tumors [71, 72]. In the literature,
other tumors, including pituitary adenomas [13], pancreatic
islet cell tumors [68, 93], reticulum cell sarcomas [69], Ewing’s
sarcomas, osteogenic sarcomas [65], carcinomas of the kidney
and urinary tract [20, 87], and giant cell tumors of bone [16],
have been reported to be associated with BK virus. In some
studies, BK viral DNA was found integrated into the host genome; in other studies, it was found to be merely episomal. It
should be noted, however, that BK viral DNA can be present
episomally in BK virus–transformed human cell lines [119,
122]. Because of the ubiquity of BK viral infection and the
variable location of the DNA within the cells, a few investigators
have questioned the association of these tumors with BK virus
[71, 73–77]. Because of the amount of negative evidence, it is
difficult to consider BK virus to be the causative agent of any
human cancer. In fact, one tumor type that was previously
associated with BK virus, Kaposi’s sarcoma [18], is now thought
to be caused by human herpesvirus type 8 [123, 124].
Although it is not proof of causality, the strongest data, including demonstration of viral DNA integration into tumor
cell genomes, and even the findings of some in situ studies,
support a correlation between BK virus and many brain and
urinary tract tumors [66, 70, 87].
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BK VIRUS AND NEOPLASIA
General mechanisms for neoplasia. There are many proposed mechanisms for BK virus–induced neoplasia, as was recently described in a review by Imperiale [125] (table 1). Some
researchers have found that BK virus T antigen can bind to
and functionally inhibit p53 and the p53-mediated response to
DNA damage in vivo and in vitro [82]. Also, there are data
that show T antigen can bind and inhibit pRb tumor–
suppressor gene products in vitro, either by directly [83] or
indirectly [84] binding pRb. Other in vivo studies demonstrate
that T antigen can induce serum independent cell growth and
the expression of free E2F, which is a protranscriptional protein
[82, 84]. These findings have found additional support in studies of human neuroblastoma tumors, which once again have
demonstrated the binding of the BK virus T antigen and p53
in situ [70].
Other researchers that have observed the same phenomenon
from a different perspective have examined the association of
BK viral infection with an increased number of chromosomal
aberrations. The induction of chromosomal aberrations via BK
virus T antigen is observed in vitro in human fibroblast cell
lines [85]. Also, one study reported that a group of patients
with polyomavirus infection who were exposed to radiation
experienced a greater number of chromosomal aberrations than
did a similar group of persons without infection [86].
Sequence variability. A topic that is often discussed in the
literature about BK virus–related neoplasia is the variability
noted among strains of the virus [17, 126–132]. These unique
strains have been characterized ever since BK viral DNA was
first fully sequenced [133]. A great deal of recent work centers
on the various strains of BK and the differences in the transcriptional control region, as was recently reviewed by Moens
et al. [132]. Knepper and diMayorca [20] examined BK viral
DNA that was isolated from a healthy liver and a kidney carcinoma. They found that the BK viral DNA isolated from the
kidney carcinoma had overrepresented promoter and origin
regions, which suggests that transformation may follow DNA
rearrangement [20], as is seen with other human DNA viruses,
namely hepatitis B and CMV [134, 135]. Although there is
disagreement [136], a number of other studies elegantly support
the view that certain strains of BK virus are capable of contributing to the formation of unique neoplasms [65, 68, 87].
Rearrangements that lead to increased and differential pathogenicity are not limited to neoplasia [50, 137, 138]. Jin et al.
[137], building on earlier studies, have developed PCR techniques to identify 4 major strains of BK virus. Their laboratory
also noted differences in the isolated strains of BK virus among
groups of infected patients [138]. Although the associations
were not strong enough to lead to any definitive conclusions,
they suggest that certain strains of virus may require certain
host susceptibilities for infection. Another study found a mutation in BK viral DNA associated with tubulointerstitial ne-
BK VIRUS AND NEUROLOGIC DISEASE
Before a discussion of BK virus and neurologic disease can happen, some background information must be provided regarding
the related papovavirus, JC virus, because the literature about
both viruses is intimately linked. JC virus is the etiologic factor
in PML [2, 141, 142]. Its presence in the CSF of patients who
are suspected of having PML, as detected by PCR, is rather
specific (range of specificity, 83%–100%) [12, 143–150], depending on the technique that was used in the study. JC viral
DNA has also been detected in specimens of brain tissue obtained
from patients without PML, which suggests that the virus has a
latent phase [12, 27, 30, 31, 146, 151–154]. The reported prevalence of latency is as high as 68% [30]. The authors of other
studies disagree with the concept of JC viral latency in the brain
and propose that JC virus is only found in the samples of brain
tissues obtained from patients with PML [14, 25, 32, 155, 156].
The literature about BK virus has a similar history: some
studies support [12, 15, 16, 27] and other studies refute [26,
30–32] theories regarding the possibility of BK viral latency in
brain tissue. The studies that were able to detect BK viral DNA
consistently in specimens of brain tissue used PCR assays as
the sole technique. The percentage of specimens of brain tissue
obtained from patients without HIV and PML that tested positive by use of PCR ranged from 20% [27] to 100% [16]. Vago
et al. [12] detected BK virus DNA by use of PCR in specimens
of brain tissue of 2 of 13 HIV-infected patients who had PML
and 1 of 16 HIV-infected patients who did not have PML. It
is likely that the differences between the laboratory findings
can be explained by the differential sensitivity of the assays that
were used in each of the laboratories. It is known that BK viral
DNA is present in very low copy numbers, from 1 to 20 genome
equivalents per 200 cells [27]. These low numbers may lead to
false negative results, depending on the size and the quality of
the sample that was tested, especially for ISH studies. Therefore,
it is predictable that we were unable to find a study in the
literature that had ISH data to support the concept of BK viral
latency in the brain.
There are a number of arguments against the concept of
latency that explain the presence of BK virus in the brains of
healthy people. One argument is that the presence of BK viral
DNA, as demonstrated by use of PCR, may have been the result
of contamination by peripheral blood leukocytes, which BK
virus is known to inhabit [16, 21–23]. It is unclear how much
this observation affects the interpretation of the literature regarding BK virus. In light of the difficulties in obtaining ISH
evidence and the potential for contamination, we believe that
there is not yet enough data to conclude that BK virus can
remain latent in the brains of both healthy persons and immunosuppressed persons. Further investigation is required to
either support or refute the concept of viral latency in the brain
for BK virus and other viruses, including JC virus.
BK viral DNA has only rarely been reported in samples of
CSF; this is not true of JC virus, which is common in the CSF
samples obtained from patients with PML. To our knowledge,
there are 4 cases reported in the literature that do not have
CSF data, and there are 3 recent reports that demonstrate evidence of BK viral DNA in the CSF [19, 49, 89, 150].
There are 2 reports from 1977 that mention BK virus in
association with neurologic symptoms, but CSF analysis is not
included in the reports. One article reviewed 3 cases of BK
virus seroconversion (as determined by a rise in IgM BK virus–specific antibodies in the serum), associated with neurologic symptoms. One patient was a 3-year-old child with the
symptoms of an upper respiratory tract infection and convulsions [92]. The other 2 patients experienced serologically determined BK viral primary infection at the ages of 33 and 45
years. Both of these patients had the symptoms of a respiratory
infection, and it is interesting to note that both patients developed an acute inflammatory polyradiculopathy [92]. The
second study from 1977 described a recipient of a bone marrow
transplant who developed BK viruria and neurologic symptoms
[157]. The report is somewhat confounded by the concurrent
presence of CMV infection and the lack of description of the
BK Virus • CID 2001:33 (15 July) • 197
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phritis that leads to end stage renal failure. The authors suggest
that this mutation may have led to the increased virulence of
BK virus [50].
Viral trans activation. Another mechanism to increase
virulence is via trans activation, either by native cell proteins
or proteins produced by other viruses. Much of the early work
on this topic centered on the SV-40 virus, the simian counterpart to JC and BK viruses. However, one group of researchers
looked specifically at BK virus: Moens et al. [88, 89] demonstrated indirect interaction between the large T antigen of BK
virus and native cell estrogen receptors that, via trans activation,
enhances the promoter of BK virus. The researchers postulated
that there was a hormone-mediated association with BK virus
reactivation and even neoplasia, although the relationships have
yet to be fully elucidated.
Trans activation also may play a role in interactions between
HIV and BK that lead to an increased expression of HIV DNA
[139]. The relationship of concomitant HIV infection with BK
virus and neoplasia has also been explored. There is in vitro
evidence to suggest that an interaction between intracellular
HIV-1 Tat protein and BK viral DNA may lead to hyperplastic,
dysplastic, and metastatic lesions in mice [78–81]. Tada et al.
[140] hypothesize that HIV plays a role in the trans activation
of many DNA viruses, and vice versa, which may explain the
prevalence of unique virus-mediated complications of HIV infection in addition to the degree of immunosupression caused
by HIV itself.
BK VIRUS AND TREATMENT
To date, there is little in the literature concerning the treatment
of patients with BK viral infection. One of the few, more-recent
reports discussed treatment in a retrospective study of children
with hemorrhagic cystitis after they underwent bone marrow
transplantation [46]. The treatments are based not on the cause
but rather the effect of the viral infection. A study of interstitial
nephritis in patients who had undergone kidney allograft trans-
198 • CID 2001:33 (15 July) • Reploeg et al.
plantation found that reducing the dose of immunosuppressive
therapy is currently the best therapeutic approach [55]. Theoretically, decreasing the amount of immune suppression, if it
present from any cause, would lead to better host clearance of
the virus. This therapy has obvious deleterious implications
regarding one of the largest groups of patients affected by BK
virus—renal and bone marrow transplant recipients—and,
therefore, this therapy is limited in its application. However,
in patients with HIV, improved control of HIV infection by
use of highly active antiretroviral therapy should lead to decreased BK virus–associated symptoms. To date, this has yet to
be shown in any studies.
CONCLUSION
Nearly 3 decades of research have led to only a minimal understanding of BK virus and its pathophysiology. This fact attests to the elusive nature of viruses and the challenge they
pose to their investigators. From the information we have, it
appears that humans are nearly universally exposed to BK virus
in childhood with minimal symptoms. Although the data are
largely epidemiological and circumstantial, BK virus is likely
transmitted via the respiratory route. After a patient has primary infection, BK virus can remain latent in many tissues,
including the kidney and possibly the brain. States of relative
or absolute cellular immunodeficiency may lead to viruria or
reactivation disease. Also, as is apparent from the neoplasia
literature, viral coinfection and trans activation may play a role
in reactivation disease and even in tumor induction.
We believe that BK virus is most often permissively present
in sites of disease in immunosuppressed patients, rather than
being an etiologic agent that causes symptoms or pathologic
findings. The strongest evidence for a BK virus–associated disease exists for hemorrhagic cystitis and BK virus–associated
nephritis, especially in recipients of solid organ or bone marrow
transplants.
BK virus can now be identified by use of specific and sensitive
techniques. A careful evaluation of the clinical and pathologic
presentations of patients with BK virus will allow us to form
a clearer picture of virus-associated pathophysiology in other
organ systems, including the liver, lungs, eyes, and CNS, and
in other disease processes, including neoplasia.
Acknowledgments
We thank Dr. Sandra C. Paek, Dr. Paula K. Raybuck, and
Nancy Green for their assistance in the preparation of this
article.
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neurologic symptoms. Although the connection between BK
virus and neurologic symptoms is loose, these are some of the
few appearances in the literature of this association.
The first more-recent case of neurologic symptoms associated
with BK virus was from 1993, when BK virus was identified as
the causative agent of subacute meningoencephalitis in a 27year-old man with hemophilia type A and AIDS [19]. The patient
was also noted to have a tubulointerstitial nephropathy, interstitial desquamative pneumonitis, and evidence of internal hydrocephalus 14 weeks before he died. Histologic examination
that involved ISH and IHC proved that BK virus was present in
the brain, kidneys, and lungs of the patient. Then, in 1996, BK
virus primary infection was seen in a 34-year-old immunocompetent man with encephalitis whose serologic status, as determined by IgM titers, was consistent with primary infection [91].
It should be noted that a biopsy was not performed, so there is
no tissue-related evidence to support this case. This same pattern
of more-severe, adult-acquired primary infection can be seen
with other viruses, such as varicella [158]. Finally, in 1999, BK
virus was implicated in another case of meningoencephalitis, this
time involving a 26-year-old homosexual man with AIDS [49,
150]. In the 10 months preceding his death, the patient developed
bilateral atypical retinitis and nephritis. Microscopic examination
of the brain showed thickened, fibrotic leptomeninges, a finding
that is characteristic of BK virus–induced pathologic findings,
whereas the underlying cortex showed mild astrocytosis. The
periventricular regions showed small patches of destroyed ependyma, and the choroid plexus was noted to be fibrotic. The
presence of BK virus was determined by use of PCR, ISH, and
IHC in the brain, kidneys, and retinal tissues. Of note, there were
no signs of HIV-related encephalopathy. In all the aforementioned recent cases, the results of PCR for other viruses (CMV,
herpes simplex virus, JC virus, and Epstein-Barr virus) and the
results of assays for related CNS infections were all negative, with
the exception of a presumed peripheral blood mononuclear cell
contamination of CMV in the retinal tissues of the patient described by Bratt et al. [49]. These cases provide evidence of a
strong association, but not proof of a causal relationship, between
these disease processes and BK virus, especially in the absence
of other agents known to infect the CNS.
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