The two human polyomaviruses BKV and JCV are associated with persistent infection and diseases of the urogenital tract and the central nervous system (CNS). Induction of disease by the viruses is regularly linked to states of im-munoincompetence. The most prominent underlying complications are AIDS and lymphoproliferative disorders. Moreover, iatrogenic immunosuppression in the course of transplantation or therapy of autoimmune disorders can contribute to polyomavirus-induced disease. Clinically overt disease usually correlates with enhanced activity of viral expression in the target organ of viral persistence. Detailed analysis of BKV- and JCV-associated diseases disclosed a variety of organs and cell types to be susceptible to virus infection. These observations fostered multiple studies on the molecular basis of polyomavirus persistence in the infected host. However, despite the availability of very sensitive techniques to discover virions and/or viral products in tissue, body fluids, or cells from infected persons, essential questions with respect to involvement of distinct organs and cell types in polyomavirus persistence are far from being answered unequivocally.
Urogenital Diseases Associated with BKV and Asymptomatic Infection. BKV is a urotheliotropic virus, which was originally detected in the urine of a patient with ureteral stenosis after renal transplantation (RT) (Gardner et al., 1971). Nevertheless, studies from recent years suggest that interstitial tubular nephritis is the most frequent BKV-associated disease after RT (Mathur et al., 1997; Pappo et al., 1996; Purighalla et al., 1995). Clinical features may mimic graft rejection or drug toxicity (Binet et al., 1999; Randhawa et al., 1999), but histopathologic examination almost always shows interstitial infiltrates of plasma cells and lymphocytes, interstitial fibrosis, tubular atrophy, and large intranuclear inclusions in tubular epithelial cells. Cells of the transitional bladder epithelium were identified as target cells for BKV infection (Gerber et al., 1980). Virus isolation, DNA detection by polymerase chain reaction (PCR), electronmicroscopy, immunohistologic staining of BKV proteins, and in situ hybridization (ISH) suggests an etiopathologic role of the virus in about 5% of RT patients (Binet et al., 1999; Randhawa et al., 1999). With the introduction of new immunosuppressive strategies, the incidence of BKV-associated complications in RT increased further, thus confirming the close relationship between excessive virus growth and immunologic impairment.
Renal failure due to BKV infection is diagnosed in patients with underlying lymphoma, hereditary immunodeficiencies (de Silva et al., 1995; Rosen et al., 1983), in renal transplant patients (Mathur et al., 1997; Pappo et al., 1996; Purighalla et al., 1995), and with AIDS (Bratt et al., 1999; Nebuloni et al., 1999). Interstitial inflammation and focal necrosis of tubular epithelium with enlargement of tubular epithelial cells and the pelvic urothelium accompany this rare complication. Aggregates of viral particles within nuclei of renal tubular cells (Rosen et al., 1983) confirm susceptibility of the urogenital tract epithelium for BKV infection.
Hemorrhagic cystitis (HC) is a serious BKV-associated complication of bone marrow transplantation (BMT) patients. Prevalence of HC varies from 10% to 68% and leads to severe hemorrhage in about 25% of bone marrow recipients (Arthur et al., 1985; Azzi et al., 1994; Bedi et al., 1995; Chan et al., 1994; Cotterill et al., 1992). Hemorrhage and viruria most likely are due to viral activation in the uroepithelium, as virus particles can be detected in exfoliated urinary cells by means of electron microscopy (Hiraoka et al., 1991). Prolonged hematuria is associated with severe morbidity and increasing viral load in urine (Azzi et al., 1999).
In patients with AIDS, systemic BKV-associated disease involves infection of the CNS, the lung, the eye, and the kidney (Bratt et al., 1999; Hedquist et al., 1999; Nebuloni et al., 1999; Smith et al., 1998; Vallbracht et al., 1993). Concomitantly with multiple lesions in the entire nephron, an interstitial tu-bulonephritis is seen. Desquamated tubular cells that display focally enlarged, eosinophilic nuclei carry BKV particles and express viral products (Cubukcu-Dimopulo et al., 2000; Nebuloni et al., 1999; Vallbracht et al., 1993). Investi gation of tubular cells at the subcellular level revealed the presence of virions in cytoplasmic reticular cisternae (Nebuloni et al., 1999), and virus-specific antigen was located in nuclei and cytoplasm (Nebuloni et al., 1999; Smith et al., 1998). Interstitial clustering of CD68-positive cells with cytoplasmic staining of virus-specific antigens indicated uptake of the virus by phagocytotic cells (Nebuloni et al., 1999). Further analysis at the ultrastructural level detected characteristic viral particles, which occasionally formed dense crystalloid arrays, thus confirming viral presence in these cells (Smith et al., 1998).
In contrast to renal disease under severe immunoincompetence, BKV infection in other patients is most likely in an asymptomatic state. In the course of lymphoproliferative diseases a clinically silent BKV-specific involvement of the urothelial tract has been reported. Virus DNA is distributed in small foci throughout the cortex and medulla of the kidney (Heritage et al., 1981), affecting renal epithelial cells and lining cells of ureter and bladder as demonstrated by BKV-specific immunostaining. In asymptomatic tissue BKV DNA persists in episomal form, and exfoliated cells carry intranuclear inclusions containing BKV antigen (Shinohara et al., 1993; Zu Rhein and Varakis, 1974). The rate of infection varies from 13% (Chesters et al., 1983) to more than 50% (Dorries and Elsner, 1991). This may depend on the study groups, which included patients with underlying diseases ranging from carcinoma and leukemia to inflammatory diseases, coronary heart disease, and multiple injuries from traffic accidents.
Thus far, no data are available on BKV in kidney tissue in the course of pregnancy. However, there is a study addressing the question of transplacental transmission of BKV in humans using tissue specimens from aborted fetuses and placenta. BKV DNA was detected by PCR in 60% of fetal kidney and in 80% of placenta samples. In maternal tissue from a control group with normal pregnancies, BKV was detected in 50% of the samples (Pietropaolo et al., 1998). Besides the finding that BKV might be transmitted vertically, the enhanced detection rates after abortion point to an activated BKV infection and a prevalence of persistent virus infection in about 80% of the population.
Analysis of prostate biopsy specimens for BKV revealed virus DNA in 58% of asymptomatic tissue and in 87% of prostate hyperplasias sampled from prostate carcinoma patients. This was comparable to the rate in bladder tissue. In addition, 70% of cervix and vulvar tissue exhibited viral DNA, and analysis of sperm gave an incidence of 95% for the presence of BKV DNA. In contrast, DNA of the second polyomavirus JC was found in only 5% of cervical and vulvar tissue specimens. Glandular tissue yielded no JCV DNA, whereas 21% of sperm samples were positive for JCV DNA. The high rate of BKV DNA present in asymptomatic tissue and semen suggests that these sites should be considered as locations of polyomavirus persistence (Monini et al., 1995, 1996; Shinohara et al., 1993).
Activation of BKV Infection in the Urogenital Tract. Virus infection of the kidney following viruria probably occurs at the time of primary infection in children (Di Taranto et al., 1997). Beyond childhood, viruria is more likely due to activation of persistent renal infection than to primary infection or reinfection. Virus products in the urine at different stages of immunologic incompetence and a high level of viruria in asymptomatic infection (Arthur et al., 1989; Coleman et al., 1980; Hogan et al., 1980; Kitamura et al., 1990; Reese et al., 1975) are strong indications for a relationship between immunodeficiency and polyomavirus activation.
The role of HIV-related immunodeficiency in BKV-associated viruria was analyzed in patients without BKV-associated diseases. Virus DNA was detected by PCR at a rate of 37-44% in the United Kingdom, Italy, and Tanzania (Agostini et al., 1995; Degener et al., 1997; Jin et al., 1995; Knowles et al., 1999). Lower rates of 20-24% were found in North America and Norway (Markowitz et al., 1993; Shah et al., 1997; Sundsfjord et al., 1994a). However, in all study groups an increase of BKV viruria under AIDS was reported on a basis of less than 8% in normal individuals. Staging of HIV patients according to their immune status revealed an inverse relationship of decreasing T-lymphocyte count and increasing viruria (Jin et al., 1995; Knowles et al., 1999; Markowitz et al., 1993; Shah et al., 1997; Sundsfjord et al., 1994a). From these studies it appears likely that BKV activation in the urinary tract under AIDS is correlated with the state of immunoincompetence. Contrasting reports with 6% BKV viruria in AIDS and AIDS/PML patients as detected by nested PCR technique could probably be explained by technical differences between laboratories (Brouqui et al., 1992; Ferrante et al., 1997).
Viruria in BMT patients was reported as early as 1975 (Reese et al., 1975). Although before transplantation only 1% of patients shed BKV (Arthur et al., 1985), increases have been reported to 22%, 48% (Arthur et al., 1988, 1989; Cotterill et al., 1992; Jin et al., 1993), 67% (Jin et al., 1995), and even 100% of patients in the post-transplant period if classic methods were combined (Gibson et al., 1985). With the advent of the more sensitive PCR, the prevalence of viruria was found to be continuously higher, ranging from 50% to 100%, if multiple samples from one patient were analyzed (Azzi et al., 1994, 1996; Bogdanovic et al., 1994; Flaegstad et al., 1991). BKV viruria often began 29 weeks after transplantation. The duration was variable and resolved spontaneously after several weeks of shedding. Virus excretion was not related to graft-versus-host disease, thus revealing that viruria after BMT is a normal asymptomatic activation event of a persistent BKV infection that often is not associated with disease. However, the involvement of BKV in hemorrhagic cystitis in about 20% of allogeneic BMT patients (Azzi et al., 1994) prompted a study of microscopic hematuria (Chan et al., 1994). Viruria in 51% of BMT patients in a 4 month period after transplantation was closely associated with hematuria in about half of the patients (Chan et al., 1994; Jin et al., 1995). Similar to asymptomatic virus shedding, most episodes of hematuria were self-limiting. From these findings it can be suggested that BKV infection after BMT is usually activated to a detectable level of virus load in the urine and might even progress to histologic destruction before virus growth comes under control.
The first carrier of a BKV infection to be described (Gardner et al., 1971) had polyomavirus viruria after RT. Virus particles were characterized by electron microscopy and virus isolation. The virus sometimes affected epithelial cells of both the recipient and donor tissues (Coleman et al., 1973). In contrast to BMT or pregnancy, after renal transplantation primary polyomavirus infection, as defined by antibody titer rises, appears to play a role by introduction of the virus into the recipient by an infected donor (Andrews et al., 1983, 1988; Arthur et al., 1989). The prevalence of polyomavirus viruria ranged from 0% to 47% in early reports, the majority of patients being asymptomatic. Even the use of PCR did not enhance the rate of detection (Sundsfjord et al., 1994a). The discrepancies among the studies might be associated with the lower sensitivities of early methods, but highly variable therapeutic schemes may also contribute to the findings (Lecatsas et al., 1973; Shah et al., 1974). In addition, examination of multiple samples revealed an intermittent and sporadic course of virus excretion as well as a highly variable duration of viruria, ranging from periods of several weeks to years. Observations over more than 3 years revealed a prevalence of 44% viruria in all patients studied. Molecular characterization of the polyomavirus species suggested that BKV viruria was more prominent in RT patients than JCV viruria (Arthur et al., 1989; Boubenider et al., 1999; Gibson and Gardner, 1983). However, viruria often was unrelated to changes in the clinical condition or treatment or even to ureteric obstruction, demonstrating that viruria might not necessarily be associated with RT (Andrews et al., 1988; Arthur et al., 1989).
Under other immunosuppressive conditions viruria often is intermittent, with sparsely distributed infected cells in urine pointing to a rather low rate of activation. Jin et al. (1993) studied a group of patients after cardiac transplantation together with BMT patients. BKV was detected in 50% of the BMT patients and in 25% of the cardiac transplantation group. In all cases excretion was intermittent and sparse and was more often correlated with older age and more aggressive underlying disease. Activating therapeutic influences in these patients could not be stated. Besides the obvious correlation with age, the data further corroborate severe immunoimpairment as a factor for activation and urinary excretion (Hogan et al., 1983; Jin et al., 1993).
In patients with autoimmune diseases in Taiwan, about 40% were found by PCR to be excreters of polyomaviruses. Interestingly, in 15%, double infections were detected, but none was positive for BKV viruria alone (Chang et al., 1996a). Further extension of the study confirmed the lack of BKV viruria in Taiwan (Tsai et al., 1997). In contrast, patients from Scandinavia with systemic lupus erythematosus had higher levels of BK viruria than healthy control subjects, whereas JCV shedding was in the range of the normal sex-matched control group. In a follow-up study, the authors found a high prevalence of intermittent or even continuous shedding of BKV at 1 year. Immunosuppressive drugs such as corticosteroids, azathioprine, cyclophosphamide, and/or metho-
trexate did not influence the kinetics of virus shedding (Rekvig et al., 1997; Sundsfjord et al., 1999). Clearly, an autoimmune disease is able to activate a persistent BKV infection to an extent that is not observed in normal individuals.
Pregnancy is the most common condition of altered immunocompetence that has been linked to polyomavirus activation (Coleman et al., 1980; Lecatsas et al., 1981). The onset of virus excretion is related to time of gestation, most often occurring late in the second and during the third trimester. Once established, excretion continues intermittently to term and might even extend into the postpartum period (Coleman et al., 1980; Gardner and Knowles, 1994). Serologic studies revealed that excretion in pregnant women is usually the result of virus activation of a persistent infection. Although activation of infection had no clinical significance (Arthur et al., 1989), women excreting polyomaviruses had more illness before and during pregnancy and may have underlying diseases such as diabetes and sarcoidosis (Gardner and Knowles, 1994). When BKV and JCV viruria were differentiated, BKV excretion rates of 15-25% were observed (Jin et al., 1993; Markowitz et al., 1991). The incidence of JCV viruria in the same geographic regions was about 7% (Gardner and Knowles, 1994; Markowitz et al., 1991), clearly demonstrating a higher incidence of BKV than JCV activation. With more advanced PCR techniques, the incidence of BKV viruria was 47% in 40 pregnant women compared to 19 healthy adults with no viruria (Jin et al., 1995). Similar to the findings in patients with systemic lupus erythematosus, in Taiwan an incidence of about 3% of BKV excretion was reported in pregnancy on the basis of 26% JCV positive urine samples and 6.5% of samples with double infections (Chang et al., 1996b; Tsai et al., 1997). This suggests that BK viruria is generally less pronounced in Taiwan than elsewhere.
Asymptomatic immunocompetent patients and healthy individuals were often included as control groups in studies of polyomavirus excretion. In contrast to the above-mentioned basic diseases and the pregnant state, the prevalence of BKV excretion during immunocompetency ranged from 0% (Bogdanovic et al., 1994; Degener et al., 1997; Jin et al., 1993, 1995; Sundsfjord et al., 1994a; Tsai et al., 1997) to about 18% (Arthur et al., 1985, 1989; Azzi et al., 1996; Kitamura et al., 1990; Markowitz et al., 1993; Shah et al., 1997). The exception is a study by Azzi et al. (1999) on BMT and hemorrhagic cystitis patients, who found a prevalence of 40% BKV excretion in 62 immunocompetent patients. The group was not further described with respect to age or possible risk factors, and a study on JCV was not performed. However, in comparison with BMT patients, the virus load in immunocompetent individuals was low (in the range of <1.2 X 104 genome copies in 5-10 ml urine). Although the sensitivity of the test system was not higher than that published before, the DNA amount in the urine suggests that asymptomatic BKV activation in immunocompetent adults is limited. This corresponds to a study reporting a low concentration of BKV DNA (<1 pg/ml) in general (Kitamura et al., 1990). Although a correlation between age and BKV excretion in adults was not apparent, in Japan detection rates in those older than 60 years were higher than in younger age groups (Kitamura et al., 1990).
Because of the prevalence of renal infection and urinary excretion it appears likely that common diseases and their associated immune responses play a role in virus activation. Whereas in immunocompetent individuals the rate of infection did not exceed 18%, impairment of the immune response in pregnancy and cardiac transplantation is linked to an activation in about 25% of individuals. In RT and AIDS patients expression is further affected to a rate of 47% at maximum. The most prominent activation processes can be observed in BMT patients. BKV expression after BMT appears to be almost always activated to a high virus load in the urine combined with an asymptomatic state of infection. Due to as yet unknown factors, which may involve host genetics, differences in therapy, or influences by the donor marrow, the infection may further be activated to a stage of cytolytic infection and hematuria without clinical symptoms.
It is conceivable that expression of the virus could be limited by the immune response, or it may, depending on the state of immunoimpairment, proceed unaffected to symptomatic disease. The amount of urinary virus in healthy individuals was regularly lower than that in immunoincompetent patients. This argues for a persistent BKV infection that is progressing stepwise from the latent or attenuated basic state of persistent infection with a rather low virus load that might even be out of the limits of detection. If the virus-specific immune response is impaired, increasing virus load and dissemination could indicate further stages of activation, ultimately leading to fatal disease.
Localization of JCV in the Urinary Tract. In contrast to BKV, JCV was never described as an etiologic agent in a urogenital disorder. Evaluation of the state of renal JCV infection in PML, the only JCV-associated disease, regularly disclosed no histopathologic changes in kidney tissue (Dorries and Els-ner, 1991). Nevertheless, a prevalence rate of renal JCV infection in PML patients between 50% and 100% was reported (Ault and Stoner, 1994; Dorries and terMeulen, 1983; Grinnell et al., 1983a; Newman and Frisque, 1997; White et al., 1992). JCV DNA is distributed in small foci throughout renal cortex and medulla (Chesters et al., 1983; Dorries and terMeulen, 1983; Grinnell et al., 1983b; McCance, 1983; Tominaga et al., 1992). The major site of infection is localized to the epithelial cells lining the collective tubules (Dorries and terMeulen, 1983). Isolated cells carry virions in nuclei and cytoplasm. Southern blot analyses in combination with cloning experiments revealed episomal JCV genomes in affected cells without evidence for integrated DNA (Chesters et al., 1983; Dorries and Elsner, 1991).
Compared with PML patients, randomly selected individuals and cancer patients had renal infections less often, and their viral loads in the organ were considerably lower (Chesters et al., 1983; Dorries and terMeulen, 1983; Grinnell et al., 1983a). The presence of JCV DNA in about 50% of kidney samples is contrasted with only 2% of samples being positive for JCV protein. This most likely reflects differences in the sensitivities of the techniques applied rather than a true difference in the activation rates of the virus. Recent PCR analyses suggest that JCV DNA is regularly detected in the kidney of more than 50% of individuals (Aoki et al., 1999). This finding and the fact that primary renal infection with JCV occurs during childhood (Bordin et al., 1997; Grinnell et al., 1983a; Newman and Frisque, 1997, 1999) support the thesis that JCV persistence is most likely established during primary infection followed by an accumulation of virus in the tissue by repeated activation throughout life.
Activation of JCV Renal Infection. Like BKV, JCV DNA is more frequently detected in the kidneys of immunoincompetent individuals than in im-munologically healthy persons. Under HIV infection urinary excretion was found to be a frequent event, ranging from 16% to 38% of patients in Europe, North America, and Africa (Agostini et al., 1995, 1997; Degener et al., 1997; Ferrante et al., 1997; Knowles et al., 1999; Markowitz et al., 1993; Shah et al., 1997; Sundsfjord et al., 1994a). In contrast to BKV activation, the incidence of JCV viruria parallels that in the normal population. In most reports, the pattern of JCV shedding was not influenced by the AIDS status or aggressive chemotherapy (Markowitz et al., 1993; Shah et al., 1997; Sundsfjord et al., 1994a). In general, the excretion rate was found comparable to that of normal individuals, being either stable or transient with identical genotypes shed in a period of 1-6 month. The frequency of excretion with increasing age did not differ significantly from that in HIV-negative individuals (Agostini et al., 1997). Obviously, JCV activation in the urinary tract is not influenced by HIV-induced immunoimpairment or therapeutic intervention for AIDS.
Similarly, JCV excretion is an uncommon event after BMT, occurring in about 5% of patients (Arthur et al., 1988; Gardner and Knowles, 1994; Myers et al., 1989; O'Reilly et al., 1981). Even sensitive PCR techniques did not change the basic findings (Azzi et al., 1994, 1999; Bogdanovic et al., 1994). Given the low frequency of viruria, JCV infection is even less active in BMT-associated immunoimpairment than BKV infection under comparable clinical conditions (Arthur et al., 1988; Gardner and Knowles, 1994). Compared with BMT, the frequency of JCV viruria after RT is higher, ranging from 18% to 57% (Gardner and Knowles, 1994; Hogan et al., 1980; Sundsfjord et al., 1994a; Yogo et al., 1991). Although highly variable, is seems likely that the rate of JCV activation after RT is comparable with that of BKV. Whether this is due to alteration of the JCV expression activity by factors related to the disease process or to the number of patients with activated infection is not known.
To analyze the role of CNS diseases other than PML in the activation of renal JCV infection, viruria was studied in a group of patients with multiple sclerosis (MS). PCR analysis revealed an excretion rate of 30-41% in chronic progressive MS (Agostini et al., 2000; Stoner et al., 1998). Because a control group of family members exhibited the same excretion rate, a regular influence of MS on JCV renal infection is rather unlikely. In conclusion, it can be as sumed that pathologic changes in the CNS do not necessarily influence JCV activation (Eisner and Dorries, 1992; Stoner et al., 1998).
Analysis of immunocompetent patients demonstrated a higher rate of renal activation with JCV than BKV. Lower polyomavirus excretion rates were in the range of 0-13% (Arthur et al., 1989; Degener et al., 1997; Jin et al., 1993, 1995; Tsai et al., 1997), whereas higher rates, between 20% and 52% (Agostini et al., 1997; Azzi et al., 1996; Bogdanovic et al., 1994; Kato et al., 1997; Kitamura et al., 1990; Markowitz et al., 1993; Shah et al., 1997; Stoner et al., 1998; Sundsfjord et al., 1994a), have also been reported. Although the broad range of excretion rates may reflect technical differences, in 1994 it became clear that urinary excretion of JCV in the normal asymptomatic population also depends on the age of the individuals analyzed (Kitamura et al., 1994). The rate was clearly higher in groups with higher mean ages (Agostini et al., 1996, 1997). Whereas younger adults shed up to <102 fg JCV DNA/ml, this amount increased with age to more than 5 X 103 fg JCV DNA/ml (Kitamura et al., 1994; Markowitz et al., 1993). The highest level of JCV DNA in urine specimens of the oldest age group reached more than 105 fg JCV DNA/ml (Kitamura et al., 1994). Extent and duration of excretion can be either highly variable or stable (Agostini et al., 1997). Most remarkably, the same JCV strains were identified in urine specimens from healthy persons and from patients with malignancies, cerebrovascular disease, or urologic complications over periods up to 6 years (Agostini et al., 1997; Kitamura et al., 1997). From these data it can be unequivocally concluded that JCV urinary excretion is caused by activation of a persistent virus infection.
Renal activation of JCV by diseases that are not related to severe alterations of the immune system clearly demonstrates that JCV viruria is influenced by more than the state of immunocompetence. This is consistent with the "rule'' that in PML/non-AIDS patients concomitant JCV viruria is as frequent as in the normal population (Arthur et al., 1989; Ferrante et al., 1997; Koralnik et al., 1999a; Markowitz et al., 1993). However, the level of JCV urinary excretion in immunocompetent individuals is noticeably higher than that of BKV, which rarely exceeds a concentration of 3 fg/ml urine (500 genome copies). Although excretion rates of both BKV and JCV seem tightly linked to increasing age (Kitamura et al., 1990), shedding of BKV and JCV occurs independently (Markowitz et al., 1993). This assumption is strongly supported by the fact that urinary coactivation of both viruses is a rare event (Azzi et al., 1999; Kitamura et al., 1990). Nevertheless, although not concurrently, both viruses were repeatedly detectable in urine from the same individual, suggesting that, once polyomavirus infection is established, activation processes may be induced independently and virus multiplication might then continue intermittently throughout life or at a sustained basal level.
Polyomavirus Infection in the Central Nervous System
CNS Disease Associated with BKV. In early studies, it was reported that fetal brain cells in vitro can be permissive for BKV (Takemoto et al., 1979).
However, even after the molecular detection of BKV DNA in the brain tissue of asymptomatic patients, the neurotropism of the virus was controversial (Eisner and Dorries, 1992). Soon after, the description of BKV-associated CNS diseases, subacute meningoencephalitis, and encephalitis in HIV patients confirmed the CNS as another site of BKV infection (Bratt et al., 1999; Vallbracht et al., 1993; Voltz et al., 1996). BKV could be isolated from the CSF in tissue culture, and the specificity of BKV in autopsy tissue was proven by molecular characterization and DNA sequencing. Histopathologic examination by im-munohistochemistry and ISH demonstrated BKV DNA and antigen in affected cells (Vallbracht et al., 1993). BKV infection is associated with blood vessels and fibrocytes in thickened leptomeninges. In cortex and adjoining white matter, reactive astrocytes were affected. The ventricular walls exhibited focal degeneration of the ependymal layer and affected astrocytes in subjacent brain tissue. Target cells for BKV were fibrocytes of the connective tissue, ependymal cells, endothelial and smooth muscle cells of blood vessels, infiltrating macrophages, and astrocytes, the only glial cell type involved in BKV CNS infection (Bratt et al., 1999; Vallbracht et al., 1993). It is of note that the variability of cell types involved in BKV infection is remarkably higher than that of JCV. This suggests a broader cell specificity for BKV and suggests that a large number of different cell types can be involved in BKV persistence.
Asymptomatic BKV Infection and Activation. The assumption that BKV may reach its target organs before disease suggested the presence of BKV DNA and persistent infection in the CNS of healthy and immunocompetent individuals. However, in early analyses brain tissue appeared to be free of virus (Ak-samit et al., 1986; Barbanti-Brodano et al., 1987; Chesters et al., 1983; Grinnell et al., 1983a). Likewise, brain tissue from AIDS patients found positive for JCV DNA did not reveal a trace of BKV DNA (Ferrante et al., 1995; Perrons et al., 1996). In contrast, other laboratories repeatedly reported the presence of BK viral DNA in samples from the CNS (De Mattei et al., 1995; Elsner and Dorries, 1992; Vago et al., 1996). These findings were supported by sequencing of new genomic TCR subtypes and cloning of complete virus genomes from a normal brain gene library (Elsner and Dorries, 1992). Nevertheless, compared with the frequency of JCV infection, the presence of BKV DNA in asymptomatic brain infection appears to be considerably lower. Definitive evidence on the localization of BKV in the brain and the cell type involved is not yet available.
Facts about the putative activation of BKV infection in the CNS are limited. BKV is shed in the CSF of patients with BKV-associated CNS disease, and the presence of BKV in the CSF is a diagnostic marker (Bratt et al., 1999; Vallbracht et al., 1993; Voltz et al., 1996). Spinal taps from PML patients and patients at risk for PML were screened for the diagnostic significance of JCV and were found positive for BKV DNA. Co-infection of patients with BKV and JCV is a frequent event and may be detected by PCR with a common primer pair. Because these persons were free of a typical BKV CNS disease, it is conceivable that a persistent BKV infection in the CNS might be subclin-ically activated under conditions comparable to those of JCV. Nevertheless, the overall frequency of such an event seems to be very low (Gibson et al., 1993; Hammarin et al., 1996; Perrons et al., 1996; Vago et al., 1996).
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