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Identification of a genomic subgroup of BK polyomavirus spread in European populations

¹ National Research Institute of Police Science, 6-3-1 Kashiwanoha, Kashiwa, Chiba 277-0882, Japan
² Department of Forensic Medicine, University of Turku, Turku 20520, Finland
³ Department of Internal Medicine, Turku University Central Hospital, Turku 20520, Finland
⁴ Department of Clinical Microbiology, Trinity Centre for Health Sciences, University of Dublin, Trinity College, St James's Hospital, Dublin, Ireland
⁵ National Virus Reference Laboratory, University College Dublin, Belfield, Dublin, Ireland
⁶ Department of Microbiology, Central Pathology Laboratory, St James's Hospital, Dublin, Ireland
⁷ Department of Urology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Correspondence
Hiroshi Ikegaya
ikegaya-tky{at}umin.ac.jp

	ABSTRACT

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BK polyomavirus (BKV) is highly prevalent in the human population, infecting children without obvious symptoms and persisting in the kidney in a latent state. In immunosuppressed patients, BKV is reactivated and excreted in urine. BKV isolates worldwide are classified into four serologically distinct subtypes, I–IV, with subtype I being the most frequently detected. Furthermore, subtype I is subdivided into subgroups based on genomic variations. In this study, the distribution patterns of the subtypes and subgroups of BKV were compared among four patient populations with various immunosuppressive states and of various ethnic backgrounds: (A) Finnish renal-transplant recipients; (B) Irish/English haematopoietic stem-cell transplant recipients with and without haemorrhagic cystitis; (C) Japanese renal-transplant recipients; and (D) Japanese bone-marrow transplant recipients. The typing sequences (287 bp) of BKV in population A were determined in this study; those in populations B–D have been reported previously. These sequences were subjected to phylogenetic and single nucleotide polymorphism analyses. Based on the results of these analyses, the BKV isolates in the four patient populations were classified into subtypes and subgroups. The incidence of subtype IV varied significantly among patient populations. Furthermore, the incidence of subgroup Ib-2 within subtype I was high in populations A and B, whereas that of Ic was high in populations C and D (P<0.01). These results suggest that subgroup Ib-2 is widespread among Europeans, whereas Ic is unique to north-east Asians. Furthermore, a phylogenetic analysis based on complete BKV DNA sequences supported the hypothesis that there is geographical separation of European and Asian BKV strains.

The GenBank/EMBL/DDBJ accession numbers for the sequences reported in this paper are AB254341–AB254367, AB260028–AB260034 and DQ457405–DQ457412.

	INTRODUCTION

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BK polyomavirus (BKV) is highly prevalent in human populations (Knowles, 2001). After asymptomatic infection during early childhood, BKV persists in renal tissue (Heritage et al., 1981; Chesters et al., 1983). Upon immunosuppression, renal BKV becomes reactivated and replicates efficiently, followed by the excretion of progeny viruses (Knowles, 2001). In immunocompromised patients, the reactivation of BKV sometimes results in renal dysfunction, such as BKV-associated nephropathy (Moens & Rekvig, 2001).

BKV is the only primate polyomavirus that has subtypes (I–IV) that are distinguished on the basis of differences in serological reactivity (Knowles, 2001). Jin et al. (1993a or b) proposed a genotyping method with which to classify BKV isolates. Thus, they identified a region of the VP1 gene probably responsible for serotypic differences. This region was PCR-amplified and the amplified fragments were sequenced. The determined sequences were compared to identify single nucleotide polymorphisms (SNPs) related to distinct subtypes. This method, and versions involving restriction (Jin, 1993) or phylogenetic (Takasaka et al., 2004; Carr et al., 2006) analysis, have since been used to classify the BKV isolates obtained from several countries, including England, Ireland, Tanzania, USA and Japan (Jin, 1993; Jin et al., 1993b, 1995; Agostini et al., 1995; Di Taranto et al., 1997; Baksh et al., 2001; Takasaka et al., 2004; Carr et al., 2006). The results of these studies have indicated that: (i) subtype I predominates in all geographical regions; (ii) subtype IV occurs at lower rates; and (iii) subtypes II and III occur rarely. Therefore, it appears that there is no correlation between BKV subtype and geographical region. This is in striking contrast to the established correlation between subtypes of JC polyomavirus (JCV), the related human polyomavirus, and geographical region (Sugimoto et al., 1997; Agostini et al., 2001; Yogo et al., 2004).

Takasaka et al. (2004) found that BKV isolates classified as subtype I might be subclassified into at least three subgroups (Ia, Ib and Ic) based on phylogenetic analysis, and reported that most subtype I isolates in Japanese renal-transplant (RT) and bone-marrow transplant (BMT) patients belonged to subgroup Ic according to this classification. As their finding potentially suggested that a correlation might exist between the subtype I subgroups and human populations, we attempted in this study to subclassify the subtype I isolates in four patient populations with various immunosuppressive states and from various ethnic backgrounds: (A) Finnish RT recipients, (B) Irish/English haematopoietic stem-cell transplant (HSCT) recipients with and without haemorrhagic cystitis (HC), (C) Japanese RT recipients and (D) Japanese BMT recipients. The typing sequences (287 bp) of BKV in population A were determined in this study; those in populations B–D have been reported previously (Takasaka et al., 2004; Carr et al., 2006). These sequences were subjected to phylogenetic and SNP analyses to classify the BKV isolates in each of the four patient populations. The distribution patterns of the subtypes and subtype I subgroups were compared among the four patient populations in order to examine whether the incidence of subtypes or subgroups differs among patient populations.

	METHODS

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Patient populations.
Four patient populations with various clinical states and from various ethnic backgrounds were studied: (A) 27 Finnish RT recipients, (B) 35 Irish/English HSCT recipients with and without HC, (C) 29 Japanese RT recipients and (D) 31 Japanese BMT recipients. Population A is described in this study and the other populations have been described previously (B, Carr et al., 2006; C and D, Takasaka et al., 2004).

Amplification and sequencing of the typing region of BKV.
Urine samples were collected from 101 RT patients at Turku University Hospital, Turku, Finland, with informed consent. The DNA was extracted as described previously (Kitamura et al., 1990). The 287 bp typing region of BKV was amplified from the DNA samples as described previously (Takasaka et al., 2004). The 287 bp region contained the whole effective sequence within the previously used 327 bp typing region (Jin et al., 1993a or b). Amplified fragments were detected by agarose-gel electrophoresis, purified by using Gel Filtration cartridges (Edge Biosystems) and subjected to a cycle-sequencing reaction using a BigDye Terminator cycle sequencing kit v. 3.1 (Applied Biosystems). DNA sequencing was performed by using an automated sequencer (3100 Avant DNA sequencer; Applied Biosystems).

Amplification and sequencing of the entire genome of BKV.
The entire BKV genome was amplified by using Phusion High-Fidelity DNA polymerase (Finnzymes Oy) and primers BKFu-IF and BKFu-IR. BKFu-IF was 5'-GGGGGATCCAGATGAAAACCTTAGGGGCT-3', nt 1731–1759 in the BKV (DUN) genome (Seif et al., 1979), and BKFu-IR was 5'-GGATCCCCCATTTCTGGGTTTAGGAAGCAT-3', nt 1739–1710. The total reaction volume of 50 µl contained 2.5 µl urinary DNA, 1 U Phusion High-Fidelity DNA polymerase, 200 µM each dNTP, 0.5 µM primers and Phusion HF buffer supplied by the manufacturer. After initial denaturation at 98 °C for 2 min, amplification was performed for 40 cycles. The cycle profile was 98 °C for 20 s, 55 °C for 20 s and 72 °C for 4 min, with the final extension at 72 °C for 10 min. After amplification, the reaction mixtures were purified by using Montage PCR centrifugal filter devices and subjected to a cycle-sequencing reaction using a BigDye Terminator cycle sequencing kit v. 3.1 (Applied Biosystems). Primers used were a set of primers reported elsewhere (Nishimoto et al., 2006), excluding S-11 and S-12, and two additional primers: S-11n [5'-CTGAGGCCTAGCAAAACTAT-3', corresponding to nt 38–57 in the BKV (DUN) genome (Seif et al., 1979) with a few mismatches] and S12n (5'-TGAAGAAACTCTGCAATGGTG-3', corresponding to nt 4681–4701). Sequencing was carried out with an automated DNA sequencer (3130 Genetic Analyzer; Applied Biosystems).

Phylogenetic analysis.
The typing-region sequences of BKV determined in this study and those reported previously (Takasaka et al., 2004; Carr et al., 2006) were aligned by using the CLUSTAL_X program, v. 1.82 (Jeanmougin et al., 1998). The complete BKV DNA sequences determined in this and previous studies (Seif et al., 1979; Tavis et al., 1989; Chen et al., 2006; Nishimoto et al., 2006), together with that of SA-12 (a baboon polyomavirus related closely to BKV) (Cantalupo et al., 2005), were aligned similarly. From the aligned sequences, a neighbour-joining (NJ) phylogenetic tree (Saitou & Nei, 1987) was constructed by using CLUSTAL_X with Kimura's correction (Kimura, 1980). The phylogenetic tree was visualized by using the NJplot program (Perrière & Gouy, 1996). To assess the confidence level of the phylogenetic tree, bootstrap probabilities (BPs) were estimated with 1000 bootstrap replicates (Felsenstein, 1985). BPs of >70 % were considered significant (Hillis & Bull, 1993).

Statistical analysis.
Statistical analysis was performed by using a ² test with Yates correction and Fisher's exact test by using Microsoft Excel software. The significance level was set at 5 %.

	RESULTS

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Phylogenetic analysis of BKV isolates
We constructed an NJ phylogenetic tree from 287 bp typing sequences of BKV in four patient populations, A–D (Table 1), plus 12 reference sequences (Table 2). The typing sequences in population A were detected and determined in this study, whereas those in populations B, C and D have been reported previously (Takasaka et al., 2004; Carr et al., 2006). According to the resultant phylogenetic tree (Fig. 1), the BKV isolates in various patient populations were classified into four major clusters, previously designated subtypes I–IV (Jin et al., 1993a or b; Takasaka et al., 2004; Carr et al., 2006), with BPs ranging from 95 % (subtype III) to 100 % (subtypes I, II and IV). Therefore, we could classify the BKV isolates in various patient populations unequivocally into subtypes I–IV (Table 1).

View this table: [in this window] [in a new window]   Table 2. BKV isolates used as references in the phylogenetic analysis (Fig. 1)

View larger version (23K): [in this window] [in a new window]   Fig. 1. Phylogenetic tree used to classify the BKV isolates detected into subtypes and subgroups. The 287 bp typing sequences detected in the four patient populations (see Table 1) plus 12 reference sequences (Table 2) were used to construct an NJ phylogenetic tree, using CLUSTAL_X with Kimura's correction. The phylogenetic tree was visualized by using the NJplot program. Subtypes and subtype I subgroups are indicated to the right of the tree. Numbers at nodes are BPs (%) obtained for 1000 replicates.

Subclassification of subtype I isolates based on SNPs
In Fig. 1, the BPs for most subgroups within subtype I were not very high (see above) and the subgroup classification therefore required support from other approaches. We examined whether any SNPs could be found among the subtype I subgroups. Alignment of all typing sequences belonging to subtype I and used for the phylogenetic analysis (Fig. 1) generated seven SNPs at nt 1687, 1698, 1809, 1860, 1887, 1908 and 1923 (Table 3). All or most isolates classified as Ia, Ib-1, Ib-2 or Ic based on the phylogenetic analysis (Fig. 1) had the same set of nucleotides assigned to Ia, Ib-1, Ib-2 and Ic, respectively, with two minor exceptions (Table 3). One exception was the Ib-2 isolates (FIN- 9 to -18, SJH-19 and -36, MAN-1 and -7 to -9) that contained C rather than A at nt 160 [interestingly, these isolates clustered together in the phylogenetic tree (Fig. 1)]. The other exception was three Ic isolates (RYU-2, KOM-20, 24) that had A rather than C at nt 238 (Table 3). In addition, one subtype I isolate (TW-8) not subclassified by the phylogenetic analysis (Fig. 1) could not be subclassified, due to the presence of multiple mismatches in the SNP comparison to each of the subtype I subgroups (Table 3). Nevertheless, TW-8 was classified unambiguously as belonging to Ic according to a phylogenetic analysis based on complete sequences (see below). Taken as a whole, the SNP analysis confirmed the subclassification of the subtype I isolates based on the phylogenetic analysis.

The incidence of subgroups Ib-2 and Ic varied markedly among patient populations. In populations A and B, Ib-2 occurred at high rates (56 and 61 %, respectively), but Ic did not occur at all. In contrast, in populations C and D, Ib-2 did not occur at all, but instead Ic occurred at high rates (69 and 71 %, respectively). The differences observed between A and C, between A and D, between B and C and between B and D were all statistically significant (P<0.01). However, there was no significant difference between A and B or between C and D. These results suggest that the high incidence of Ib-2 or Ic is linked to the ethnic origin (i.e. European or Japanese) of the sample donors rather than to their clinical state.

Phylogenetic analysis of subtype I isolates based on complete viral DNA sequences
Nishimoto et al. (2006) recently reported 28 complete BKV DNA sequences mainly derived from the urine of Japanese RT and BMT patients (Table 5). Here, we amplified and sequenced seven complete BKV genomes from the urine of Finnish RT patients (Table 5). These sequences (n=35) and the complete sequence of baboon polyomavirus SA-12 (a polyomavirus related closely to BKV; Cantalupo et al., 2005) were aligned, and the aligned sequences were used to construct an NJ phylogenetic tree. According to the resultant tree (Fig. 2), the BKV isolates analysed were divided into three major clusters, corresponding to subtypes I, III and IV, with high BPs (100 %) (no sequences belonging to subtype II were included in the analysis, as no subtype II isolates were available). Furthermore, subtype I was subdivided into three subclusters corresponding to Ib-1, Ib-2 and Ic, with high BPs (100 %) (as only a single isolate belonging to Ia was analysed, it remained unclear whether Ia also represents a distinct clade). Ic included only Japanese isolates, whilst Ib-2 included five Finnish, one Dutch and one American isolate. In addition, two Japanese subtype I isolates (TW-8 and RYU-2), outlying on the phylogenetic tree based on typing sequences (Fig. 1), fell into the Ic cluster. These findings support our hypothesis that there is geographical separation of European and Asian BKV strains.

View this table: [in this window] [in a new window]   Table 5. BKV isolates (n=35) whose complete DNA sequences were analysed (Fig. 2)

View larger version (15K): [in this window] [in a new window]   Fig. 2. NJ phylogenetic tree relating 35 complete BKV DNA sequences. The phylogenetic tree was constructed from complete sequences, excluding regulatory sequences, by using the NJ method. The phylogenetic tree was visualized by using the NJplot program. The tree was rooted by using SA-12 (Cantalupo et al., 2005) as the outgroup. Subtypes and subtype I subgroups are indicated to the right of the tree. Symbols for sequences are shown in Table 4. Numbers at nodes indicate BPs (%) obtained from 1000 replicates.

	DISCUSSION

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Ib-2 was detected at high rates in two representative European populations, Finnish and Irish/English, that are distantly related both geographically and linguistically (Ruhlen, 1987). Therefore, it is likely that Ib-2 is widespread among Europeans. In contrast, Ic was detected at a high rate in two patient populations of a single ethnic origin (i.e. Japanese). We recently investigated the distribution of BKV subtypes and subgroups in East Asia and found that, in eastern China, the incidence of Ic is higher than the other subtype I subgroups (Chen et al., 2006). Therefore, it appears that Ic is widespread among north-east Asians.

If Ib-2 and Ic are correlated to Europeans and East Asians, respectively, it is reasonable to assume that the other subtype I subgroups, Ia and Ib-1, are also linked to specific human populations. We speculate on their origins in the following paragraphs.

Only rare Ia isolates were detected in the Irish/English patients and none were detected in the Finnish and Japanese patients (Table 4). Three reference isolates (Gardner, DUN and MM) belonged to this subgroup (Table 2; Fig. 1). One of these (Gardner) was recovered from a Sudanese RT patient and the others were from patients in the USA, where people of various ethnic origins are admixed. Based on the available information, albeit greatly limited, we postulate tentatively that Ia originally occurred among Africans. As noted above, we detected Ia isolates in four patients in population B (the Irish/English population). We confirmed that these patients were all Irish. This may imply that Ia, originally transmitted from African immigrants, is now circulating among Irish people.

Ib-1 was detected at low rates in not only European, but also Japanese, patient populations (Table 4). Furthermore, several reference isolates (GS, Dik, WW and HI-u5) belonged to this subgroup (Table 2 and Fig. 1). These isolates have been obtained in various countries, including England, the Netherlands, South Africa and the USA. Therefore, Ib-1 became widespread throughout the world, although it possibly originated in a human population that remains to be identified.

In summary, we present the first evidence that a correlation exists between two subtype I subgroups (Ib-2 and Ic) of BKV and human populations. If the distribution of subtype I subgroups in many human populations around the world can be obtained, it should elucidate an overall profile of the correlation between subtype I subgroups and human populations. In immunocompromised patients, BKV sometimes causes renal dysfunction, such as BKV-associated nephropathy (Moens & Rekvig, 2001). As subtype I is the major subtype of BKV in most human populations, the finding of a correlation between the subtype I subgroups of BKV and human populations should help further study on the relationship between the pathogenicity of BKV and human populations.

	ACKNOWLEDGEMENTS

 
We are grateful to all of the urine donors. This study was supported in part by grants from the Ministry of Health, Labour and Welfare, Japan.

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Received 11 May 2006; accepted 27 July 2006.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ikegaya, H. Articles by Yogo, Y. Search for Related Content PubMed PubMed Citation Articles by Ikegaya, H. Articles by Yogo, Y. Agricola Articles by Ikegaya, H. Articles by Yogo, Y.