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Short Communication |
1 Division of Transfusion Medicine, Department of Haematology, University of Cambridge, Cambridge, UK
2 Department of Genetics, University of Cambridge, Cambridge, UK
3 National Blood Service, Cambridge Blood Centre, Cambridge, UK
Correspondence
Daniel Candotti
dc241{at}cam.ac.uk
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ABSTRACT |
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The GenBank/EMBL/DDBJ accession numbers for the Ghanaian B19 sequences obtained in this study are AY582124, AY582125, DQ234769, DQ234771, DQ234775, DQ234778 and DQ234779.
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MAIN TEXT |
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TOPABSTRACTMAIN TEXTREFERENCES |
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). B19 infection is associated with various clinical manifestations depending on interaction between viral factors and immunological and haematological status of the host (Heegaard & Brown, 2002; Kerr, 2005). Persistent B19 infections have been documented, but their pathogenicity remains unclear (Candotti et al., 2004; Heegaard et al., 2002; Lefrere et al., 2005).
Three divergent genotypes (1–3) have been identified among B19 strains (Servant et al., 2002). The prevalence of genotype 2 or genotype 3 strains appears lower than that of genotype 1 in western countries (Cohen et al., 2006; Servant et al., 2002). Consequently, few clinical and molecular data on genotype 3 strains were available until West Africa was identified as an endemic region for B19 genotype 3 infection (Candotti et al., 2004). Limited analysis of the NS1–VP1u junction of West African strains previously suggested the presence of two potential clusters within genotype 3 (Candotti et al., 2004; Parsyan et al., 2006b). To investigate further the genetic heterogeneity of genotype 3, seven nearly full-length sequences (4866 bp) of B19 genotype 3 strains were obtained from infected Ghanaian individuals and analysed together with sequences of genotypes 1, 2 and 3 from GenBank.
Sequences were subjected to phylogenetic analysis performed with PAUP* by a neighbour-joining algorithm based on Kimura two-parameter distance estimation (Swofford & Sullivan, 2003). Complete virus-genome analysis by the maximum-likelihood and parsimony methods provided similar results (data not shown). Diversity was defined as the mean value for pairwise distance between sequences within the same group, calculated as the number of nucleotide differences between two individual sequences, corrected for sequence length. Similarly, inter-group distance was calculated as the number of nucleotide differences between every pair of individual sequences included in two different groups, corrected for sequence length. Two distinct clusters (100 % bootstrap values over 1000 replicates) were observed within the genotype 3 clade (Fig. 1). Four and seven sequences clustered with reference sequences V9 (GenBank accession no. AJ249437
[GenBank]
) and D91.1 (AY083234
[GenBank]
), respectively. The mean intra-group distances were 1.8 % (range 0.38–3.33 %) and 2.5 % (range 0.88–3.45 %). The overall mean sequence variation within genotype 3 was 3.91 % (range 0.38–5.71 %), which was significantly higher than the intra-group diversity observed within genotype 1 (mean 1.01 %, range 0.59–1.51 %) or genotype 2 (mean 1.77 %, range 0.29–2.32 %) (Table 1). The mean inter-group distance between the genotype 3 subclusters was 5.42 % (range 4.92–5.71 %), which was higher than the intra-group diversity observed in either genotype 1 or 2 and within genotype 3 subclusters. Similar inter-group distances were observed between each of these subclusters and genotype 1 or genotype 2 (Table 1). Genetic divergence was consistent over the entire genome, as indicated by analysis of the coding and non-coding regions (Table 1), except in the 7.5 kDa protein gene (not shown). On the basis of these observations, it is proposed to recognize two subtypes of genotype 3 in addition to the three main genotypes within the genus Erythrovirus and to designate these two subtypes tentatively as B19 genotype 3a (B19/3a) and B19 genotype 3b (B19/3b).
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. Due to the limited number of samples studied, the analysis was limited to a strict molecular clock. Sampling dates were available for the Ghanaian sequences. Within the B19/3a cluster, samples Gh3051, GhP227, GhP416 and GhD1599 were collected in 2002, 2003, 2004 and 2005, respectively. Within the B19/3b cluster, Gh2768 was collected in 2002 and GhP693 and GhP748 in 2004. According to published material, the V9 and D91.1 reference sequences were obtained from samples collected in 1995 and 1991, respectively (Nguyen et al., 1999; Servant et al., 2002). Sequences with GenBank accession numbers DQ408302
[GenBank]
–DQ408305
[GenBank]
were not included in the analysis because of lack of sampling date. Overall, analyses of both NS1 and VP1 datasets showed high and similar mean rates of evolutionary change, at 1.2x10–4 and 2.3x10–4 nucleotide substitution per site per year, respectively (Table 2). The substitution rate was slightly higher for VP1 than for NS1, but the difference was not significant, as the 95 % high-probability-density (HPD) intervals overlapped. The mean substitution rate of 2x10–4 nucleotide substitutions per site per year was similar to the recently reported rate of B19 genotype 1 sequences (approx. 1x10–4 nucleotide substitutions per site per year; Shackelton & Holmes, 2006). The significantly higher diversity within the whole genotype 3 group suggests that genotype 3 is more ancient than the other two genotypes. In addition, the similarity of the nucleotide-substitution rates for B19 genotype 3, genotype 1 and carnivore parvoviruses supports the hypothesis that a high mutation rate is characteristic of members of the family Parvoviridae (Lukashov & Goudsmit, 2001; Shackelton et al., 2005). Why such an elevated substitution rate is observed in a small, single-stranded (ss) DNA virus remains unclear. The similar substitution rates observed in the non-structural gene NS1 and the structural gene VP1 of the genotype 3 strains suggests that evolution is not driven primarily by immune pressure. The high level of replication (1010–1013 genome equivalents ml–1) observed during the early phase of B19 infection may contribute to this phenomenon (Heegaard & Brown, 2002). Persistent infection characterized by low but continuous virus replication over prolonged periods of time, described previously for both genotypes 1 and 3, may also contribute to accumulated mutations (Candotti et al., 2004; Lefrere et al., 2005). In some cases, it was associated with a high degree of genetic variability (Gallinella et al., 2003). The ssDNA nature of the B19 genome in itself may play a role, as similar substitution rates were reported for other ssRNA viruses (Simmonds, 2001).
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). Despite theoretical concerns regarding the general applicability of the molecular-clock assumption (Simmonds, 2001), Shackelton & Holmes (2006) considered the evolutionary history of B19 genotype 1 to be approximated adequately by the BEAST molecular-clock models because similar substitution rates were observed when using a ‘relaxed’ clock model.
A common characteristic of B19 genotypes and subtypes is a high ratio of synonymous to non-synonymous nucleotide changes per site, suggesting that NS1 and VP1/VP2 regions are under strong purifying selection (not shown) (Lukashov & Goudsmit, 2001; Servant et al., 2002). The association of high genetic diversity with low amino acid variability observed in B19 is consistent with the apparent lack of difference in pathogenicity, clinical manifestations and antigenic reactivity between genotypes (Blumel et al., 2005; Candotti et al., 2006; Gallinella et al., 2003; Parsyan et al., 2006a, b; Servant et al., 2002).
In an attempt to estimate the respective epidemiology of B19 genotype 3 subtypes, phylogenetic analysis was performed using partial NS1 and/or VP1u sequences of 53, 10 and seven genotype 3 strains isolated from Ghana (this study; Candotti et al., 2004, 2006; Parsyan et al., 2006a, b), western Europe (Nguyen et al., 1999; Servant et al., 2002) and Brazil (Sanabani et al., 2006), respectively. All genotype 3 sequences clustered in either of the two subgroups, with bootstrap values of 72 and 75 % when analysing short NS1 sequences and VP1u sequences, respectively (data not shown). Overall results showed that 62 % of sequences clustered as B19/3a and 38 % as B19/3b. B19/3a was predominant in Ghana (75 %), whereas B19/3b seemed more prevalent in western Europe (70 %) and Brazil (100 %). However, the predominance of B19/3a is based on a relatively small number of strains (n=53) collected in a restricted area. A similar distribution obtained in different groups (e.g. healthy blood donors, pregnant women or transfused children) over several years seems to eliminate the possibility of a bias introduced by an outbreak in a limited population. More detailed epidemiological information is needed to establish whether B19 genotype 3 strains in western Europe and South America were introduced recently from West Africa.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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TOPABSTRACTMAIN TEXTREFERENCES |
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Candotti, D., Etiz, N., Parsyan, A. & Allain, J. P. (2004). Identification and characterization of persistent human erythrovirus infection in blood donor samples. J Virol 78, 12169–12178.
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Heegaard, E. D. & Brown, K. E. (2002). Human parvovirus B19. Clin Microbiol Rev 15, 485–505.
Heegaard, E. D., Petersen, B. L., Heilmann, C. J. & Hornsleth, A. (2002). Prevalence of parvovirus B19 and parvovirus V9 DNA and antibodies in paired bone marrow and serum samples from healthy individuals. J Clin Microbiol 40, 933–936.
Kerr, J. R. (2005). Pathogenesis of parvovirus B19 infection: host gene variability, and possible means and effects of virus persistence. J Vet Med B Infect Dis Vet Public Health 52, 335–339.[Medline]
Lefrere, J. J., Servant-Delmas, A., Candotti, D., Mariotti, M., Thomas, I., Brossard, Y., Lefrere, F., Girot, R., Allain, J. P. & Laperche, S. (2005). Persistent B19 infection in immunocompetent individuals: implications for transfusion safety. Blood 106, 2890–2895.
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Received 25 August 2006;
accepted 27 September 2006.
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