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Journal of Virology, December 2007, p. 13254-13258, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01018-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Occurrence of the European Subgroup of Subtype I BK Polyomavirus in Japanese-Americans Suggests Transmission outside the Family

Yoshiaki Yogo,^* Shan Zhong, Makoto Suzuki, Ayako Shibuya, and Tadaichi Kitamura

Department of Urology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan

Received 10 May 2007/ Accepted 4 September 2007

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To examine the mode of transmission of BK polyomavirus (BKV), urine samples were collected from Japanese-Americans in Los Angeles and from other southern Californians. Subtype I was the main subtype found in samples from both groups. The subtype I subgroup Ib-2, which is predominant in Europe, was the primary subgroup detected in second-generation Japanese-Americans and in southern Californians; however, the Ic subgroup prevalent in native Japanese was rare in these populations. Since the European subgroup (Ib-2) predominated in the studied geographic area, the findings demonstrate that transmission outside the family is common in the spread of BKV, unlike previous findings for JC polyomavirus.

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BK polyomavirus (BKV) is ubiquitous in human populations, infecting children asymptomatically and then persisting in the kidneys (11). Renal BKV in immunocompetent individuals is not latent but replicates frequently, and progeny viruses are excreted in urine (27). In immunosuppressed patients (particularly renal transplant recipients), BKV may cause renal dysfunction such as BKV-associated nephropathy (6).

BKV isolates worldwide are classified into four subtypes (I to IV) by serological and genotyping methods (11). Subtype I (the most prevalent subtype) is further divided into four subgroups (Ia, Ib-1, Ib-2, and Ic) based on DNA sequence variations (7, 19, 25). Each of these subgroups has a unique geographic distribution pattern: Ia is prevalent in Africa, Ib-1 in Southeast Asia, Ib-2 in Europe, and Ic in Northeast Asia, including Japan (7, 19, 25). Similar to JC polyomavirus (JCV), a human polyomavirus closely related to BKV (23), it appears that subtype I BKV evolved in association with the division of human populations. However, recent studies (25, 26) have also revealed certain unique aspects of the relationship between BKV and humans, and further understanding of this relationship requires more information about BKV, including its mode of transmission.

The mode of JCV transmission has been studied using urinary JCV DNA, and it has been established that JCV is usually transmitted from parents to children during long-term cohabitation (8, 12, 18, 24). Since BKV is also frequently detected in the urine of immunocompetent individuals (27), the methods used to clarify the mode of JCV transmission should be applicable to BKV. To test the hypothesis that, similar to JCV, BKV is transmitted within the family, here we used urine samples previously collected from Japanese-Americans for the study of JCV transmission (18).

Urine samples were collected from Japanese-Americans (second and third generations) and from other southern Californians (see reference 18 for details). The Japanese-American urine donors were patients at the Nikkei Medical Center in the Little Tokyo neighborhood of Los Angeles. Their parents and grandparents were all Japanese. The urine samples from other southern Californians were collected from the general patient population at the Scripps Clinic, La Jolla, CA. This study was approved by the Human Subjects Committee of the Scripps Research Institute (protocol no. 99-047).

DNA samples extracted from urine (10) and stored at –20°C (18) were used in the study. The 287-bp BKV typing region and the entire BKV genome were amplified from the urinary DNA (2, 25), and the amplified fragments were sequenced (2, 25, 26). Neighbor-joining (NJ) phylogenetic trees (15) were reconstructed using the CLUSTAL W program (21) with Kimura's correction (9) and visualized using the NJ plot program (14). To root the trees, SA12 (a baboon polyomavirus related to BKV) (1) was used as the out-group. The confidence levels for branching patterns in the NJ trees were assessed based on 1,000 bootstrap replicates (4). Statistical analysis was performed using a chi-square test with Yates' correction and Fisher's exact test. All statistical analyses were performed with numbers of isolates rather than percentages. The significance level was set at 5%.

BKV subtypes and subgroups in southern Californians and Japanese-Americans. We detected BKV DNA in urine samples by PCR amplification of the 287-bp typing region. BKV DNA was detected in 47 of 161 (29%), 15 of 59 (25%), and 4 of 42 (10%) samples from the southern Californian, second-generation Japanese-American, and third-generation Japanese-American populations, respectively. Repeated PCR with a larger amount of the template DNA failed to increase the rate of detection of BKV in each population. We attempted to determine the sequences of the 287-bp typing regions amplified from the samples from the three populations, and we were able to obtain typing region sequences from 39 (LAB-1 to LAB-39), 14 (J2B-1 to J2B-14), and 4 (J3B-1 to J3B-4) BKV isolates from the respective populations. An NJ phylogenetic tree was constructed from these typing sequences and reference sequences representing individual subtypes and subgroups. Based on the phylogenetic tree (Fig. 1), we identified four major clusters with high bootstrap probabilities (BPs) ranging from 83 to 100%. Based on reference sequences for individual subtypes, each cluster was easily identified as subtype I, II, III, or IV (Fig. 1). In the phylogenetic tree (Fig. 1), subtype I was subdivided into subclusters, albeit with lower BPs. Based on reference isolates for subtype I subgroups, the four major subclusters were judged to correspond to subgroups Ia, Ib-1, Ib-2, and Ic (Fig. 1).

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FIG. 1. NJ phylogenetic tree classifying 57 BKV isolates into subtypes and subgroups. The 287-bp typing sequences detected in the present study (corresponding to isolate designations shown in bold) plus 17 reference sequences were used to reconstruct the NJ phylogenetic tree. The corresponding sequence of the baboon polyomavirus SA12 (GenBank accession number, AY614708) was used as the out-group. The phylogenetic tree was visualized using the NJ plot program. Subtypes and subtype I subgroups are indicated to the right of the tree. The numbers at nodes are BPs (%) obtained for 1,000 replicates (only values of >50% are shown for major nodes). Isolates with asterisks were also used to reconstruct a phylogenetic tree based on complete genome sequences (Fig. 2). The geographic origins of reference isolates were the United States (DUN), Kenya (KEN-1), South Africa (WW), Ethiopia (ETH-3), The Netherlands (Dik and JL), Finland (FNL-12), the United Kingdom (AS and GBR-12), and Japan (KOM-2, KOM-3, MT, RYU-2, RYU-3, THK-8, TW-1, and TW-3) (13, 16, 20, 25).

To ascertain the branching patterns of BKV isolates based on partial BKV genome sequences, the complete DNA sequences of 12 isolates from southern Californians, 5 from second-generation Japanese-Americans, and 1 from a third-generation Japanese-American were determined, and an NJ phylogenetic tree was reconstructed from these sequences and reference sequences. In this tree (Fig. 2), BKV sequences were divided into three major clusters with high BPs (100%), and the clusters corresponded to subtypes I, II and III, and IV. The subtype II and III cluster was further divided into two subclusters with high BPs (99 to 100%), and subtype I was subdivided into four subclusters, corresponding to subgroups Ia, Ib-1, Ib-2, and Ic (25), with high BPs (100%). In short, the phylogenetic analysis based on complete sequences confirmed both the classification of the BKV isolates into subtypes and the subclassification of subtype I into subgroups (Fig. 1).

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FIG. 2. NJ phylogenetic tree relating 35 complete BKV DNA sequences. The complete sequences determined in this study (corresponding to isolate designations shown in bold) plus 17 reference sequences were used to reconstruct the NJ phylogenetic tree. The baboon polyomavirus SA12 (GenBank accession number, AY614708) was used as the out-group. The phylogenetic tree was visualized using the NJ plot program. Subtypes and subgroups are indicated to the right of the tree. The numbers at nodes are BPs (%) obtained for 1,000 replicates (only those for major clusters are shown). Geographic origins of reference isolates are as given in the legend to Fig. 1.

Profiles of BKV subtypes and subgroups in southern Californians and Japanese-Americans. The numbers of isolates classified as belonging to each subtype for the three populations studied here and also for the native Japanese population (26) are shown in Table 1. Subtype identification was based on phylogenetic analysis (Fig. 1). Subtype I was predominant in all populations, subtype IV occurred at the second-highest rate only in native Japanese, and subtypes II and III occurred rarely or not at all in all populations. With reference to the incidence of subtype I, the incidence of subtype IV was significantly lower in southern Californians than in native Japanese (P < 0.01).

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TABLE 1. BKV subtypes detected in various populations

Table 2 shows the numbers of isolates classified into each subtype I subgroup for the three populations studied here and also for the native Japanese population (26). Subgroup identification was based on phylogenetic analysis (Fig. 1). Subgroup Ib-2 was the most prevalent in southern Californians and second-generation Japanese-Americans, and subgroup Ib-1 was the second most prevalent in both populations. In contrast, subtype Ic was the most prevalent in native Japanese, with a rate of 89%. Subgroup Ia was not detected or only rarely detected in all populations. With reference to the incidence of subtype Ic, the incidences of subtype Ib-2 and Ib-1 were significantly higher in southern Californians and second-generation Japanese-Americans than in native Japanese (P < 0.01). Thus, although the number of BKV sequences was small, particularly in samples from second-generation Japanese-Americans (Table 2), the statistical analysis supported similarity in the distribution patterns of subtype I subgroups among southern Californians and second-generation Japanese-Americans. Subgroups Ia, Ib-2, and Ic were detected in third-generation Japanese-Americans, but the incidence of these subgroups was too low to be examined statistically (Table 2).

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TABLE 2. Subtype I subgroups detected in various populations

According to a census report for San Diego County (22), in which the Scripps Clinic is located, the percentage of "white" (i.e., European-American) residents is the highest of all races, accounting for two-thirds of the population. As reported recently (7, 19, 25), each subgroup of subtype I BKV has a unique geographic distribution pattern: Ia is prevalent in Africa, Ib-1 in Southeast Asia, Ib-2 in Europe, and Ic in Northeast Asia. Therefore, if BKV accompanied emigrants to San Diego County, the European subgroup (i.e., Ib-2) should be predominant in southern Californians. In agreement with this expectation, Ib-2 was detected most frequently in southern Californians, followed by Ib-1, with rare detection of Ic and no detection of Ia. Therefore, it appears that Ib-2 strains introduced by European emigrants are circulating in the southern Californian community.

Since most Japanese emigrants reached adulthood before emigrating to the United States and BKV infection generally occurs during childhood (11), these individuals should have been infected with BKV in Japan. The infecting BKV strains (mainly of subgroup Ic) should have accompanied the emigrants to the United States, since after primary infection, BKV strains persist in the kidneys of most individuals (3, 5). If BKV is transmitted within the family, similar to JCV, then subgroup Ic would have been transmitted from generation to generation in Japanese-American families. However, Ib-2 (the subgroup prevalent among Europeans and southern Californians), and not Ic, was the main subgroup detected in second-generation Japanese-Americans. This finding suggests that transmission outside the family is common in the spread of BKV, in contrast to that of JCV.

The present findings have several implications for the epidemiology of BKV. First, we stress that the distribution of subtype I subgroups in Japanese-Americans shifted almost totally from the Japanese to the European pattern over only one generation. This suggests that the transmission of BKV infection outside the family is very efficient, which agrees with the seroepidemiological observation that most people are infected with BKV during early childhood (11, 17), whereas JCV infection continues throughout childhood (17). Second, since BKV infection occurs mainly outside the family, vertical infection (i.e., transmission from mother to offspring across the placenta, in the birth canal, and through milk) is excluded as the general mode of BKV transmission. This conclusion is meaningful since there is a debate regarding the role of placental BKV in the transmission of BKV (11).

Nucleotide sequence accession numbers. The sequences of the BKV isolates described in this article have been deposited in the GenBank/EMBL/DDBJ data library and have been assigned accession numbers AB301498 to AB301554 (typing region sequences) and AB301086 to AB301103 (complete genome sequences).

 
We are grateful to all the urine donors.

This study was supported in part by grants from the Ministry of Health, Labor and Welfare, Japan.

 
* Corresponding author. Mailing address: Department of Urology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8662. Fax: 81-3-5800-8917. E-mail: yogo-tky{at}umin.ac.jp

Published ahead of print on 12 September 2007.

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Journal of Virology, December 2007, p. 13254-13258, Vol. 81, No. 23
0022-538X/07/$08.00+0     doi:10.1128/JVI.01018-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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• Yogo, Y., Zhong, S., Xu, Y., Zhu, M., Chao, Y., Sugimoto, C., Ikegaya, H., Shibuya, A., Kitamura, T. (2008). Conserved archetypal configuration of the transcriptional control region during the course of BK polyomavirus evolution. J. Gen. Virol. 89: 1849-1856 [Abstract] [Full Text]  

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