Human parechoviruses (HPeVs) are highly prevalent pathogens among very young children. Although originally classified into two serologically distinct types, HPeV1 and -2, recent analyses of variants collected worldwide have revealed the existence of 12 further types classified genetically by sequence comparisons of complete genome sequences or the capsid (VP1) gene. To investigate the nature of HPeV evolution, its population dynamics and recombination breakpoints, this study generated 18 full-length genomic sequences of the most commonly circulating genotypes, HPeV1 and -3, collected over a time span of 14 years from The Netherlands. By inclusion of previously published full-length sequences, 35 sequences were analysed in total. Analysis of contemporary strains of HPeV1 and those most similar to the prototype strain (Harris) showed that HPeV1 variants fall into two genetically distinct clusters that are much more divergent from each other than those observed within other HPeV types. Future classification criteria for HPeVs may require modification to accommodate the occurrence of variants with intermediate degrees of diversity within types. Recombination was frequently observed among HPeV1, -4, -5 and -6, but was much more restricted among HPeV3 strains. Favoured sites for recombination were found to flank the capsid region, and further sites were found within the non-structural region, P2. In contrast to other HPeV types, the majority of the HPeV3 sequences remained monophyletic across the genome, a possible reflection of its lower diversity and potentially more recent emergence than other HPeV types, or biological and/or epidemiological constraints that limit opportunities for co-infections with potential recombination partners.


Article metrics loading...

Loading full text...

Full text loading...



  1. Abed, Y. & Boivin, G.(2005). Molecular characterization of a Canadian human parechovirus (HPeV)-3 isolate and its relationship to other HPeVs. J Med Virol 77, 566–570.[CrossRef] [Google Scholar]
  2. Abed, Y. & Boivin, G.(2006). Human parechovirus infections in Canada. Emerg Infect Dis 12, 969–975.[CrossRef] [Google Scholar]
  3. Al-Sunaidi, M., Williams, C. H., Hughes, P. J., Schnurr, D. P. & Stanway, G.(2007). Analysis of a new human parechovirus allows the definition of parechovirus types and the identification of RNA structural domains. J Virol 81, 1013–1021.[CrossRef] [Google Scholar]
  4. Baumgarte, S., de Souza Luna, L. K., Grywna, K., Panning, M., Drexler, J. F., Karsten, C., Huppertz, H. I. & Drosten, C.(2008). Prevalence, types, and RNA concentrations of human parechoviruses, including a sixth parechovirus type, in stool samples from patients with acute enteritis. J Clin Microbiol 46, 242–248.[CrossRef] [Google Scholar]
  5. Benschop, K. S., Schinkel, J., Minnaar, R. P., Pajkrt, D., Spanjerberg, L., Kraakman, H. C., Berkhout, B., Zaaijer, H. L., Beld, M. G. & Wolthers, K. C.(2006a). Human parechovirus infections in Dutch children and the association between serotype and disease severity. Clin Infect Dis 42, 204–210.[CrossRef] [Google Scholar]
  6. Benschop, K. S. M., Schinkel, J., Luken, M. E., van den Broek, P. J. M., Beersma, M. F. C., Menelik, N., van Eijk, H. W. M., Zaaijer, H. L., VandenBroucke-Grauls, C. M. J. E. & other authors(2006b). Fourth human parechovirus serotype. Emerg Infect Dis 12, 1572–1575.[CrossRef] [Google Scholar]
  7. Benschop, K., Thomas, X., Serpenti, C., Molenkamp, R. & Wolthers, K.(2008a). High prevalence of human parechovirus (HPeV) genotypes in the Amsterdam region and identification of specific HPeV variants by direct genotyping of stool samples. J Clin Microbiol 46, 3965–3970.[CrossRef] [Google Scholar]
  8. Benschop, K. S., Williams, C. H., Wolthers, K. C., Stanway, G. & Simmonds, P.(2008b). Widespread recombination within human parechoviruses: analysis of temporal dynamics and constraints. J Gen Virol 89, 1030–1035.[CrossRef] [Google Scholar]
  9. de Souza Luna, L. K., Baumgarte, S., Grywna, K., Panning, M., Drexler, J. F. & Drosten, C.(2008). Identification of a contemporary human parechovirus type 1 by VIDISCA and characterisation of its full genome. Virol J 5, 26[CrossRef] [Google Scholar]
  10. de Vries, M., Pyrc, K., Berkhout, R., Vermeulen-Oost, W., Dijkman, R., Jebbink, M. F., Bruisten, S., Berkhout, B. & van der Hoek, L.(2008). Human parechovirus type 1, 3, 4, 5, and 6 detection in picornavirus cultures. J Clin Microbiol 46, 759–762.[CrossRef] [Google Scholar]
  11. Drexler, J. F., Grywna, K., Stocker, A., Almeida, P. S., Medrado-Ribeiro, T. C., Eschbach-Bludau, M., Petersen, N., da Costa-Ribeiro, H., Jr & Drosten, C.(2009). Novel human parechovirus from Brazil. Emerg Infect Dis 15, 310–313.[CrossRef] [Google Scholar]
  12. Ghazi, F., Hughes, P. J., Hyypia, T. & Stanway, G.(1998). Molecular analysis of human parechovirus type 2 (formerly echovirus 23). J Gen Virol 79, 2641–2650. [Google Scholar]
  13. Heath, L., van der Walt, E., Varsani, A. & Martin, D. P.(2006). Recombination patterns in aphthoviruses mirror those found in other picornaviruses. J Virol 80, 11827–11832.[CrossRef] [Google Scholar]
  14. Ito, M., Yamashita, T., Tsuzuki, H., Takeda, N. & Sakae, K.(2004). Isolation and identification of a novel human parechovirus. J Gen Virol 85, 391–398.[CrossRef] [Google Scholar]
  15. Jukes, T. & Cantor, C.(1969). Evolution of protein molecules. In Mammalian Protein Metabolism, pp. 21–123. Edited by H. N. Munro. New York: Academic Press.
  16. Kapoor, A., Patel, D. D., Kumar, S., Ayyagari, A. & Dhole, T. N.(2004). Molecular characterization of echovirus 11 isolates from India. Indian J Med Res 119, 149–156. [Google Scholar]
  17. Kirkegaard, K. & Baltimore, D.(1986). The mechanism of RNA recombination in poliovirus. Cell 47, 433–443.[CrossRef] [Google Scholar]
  18. Kumar, S., Tamura, K. & Nei, M.(2004).mega3: integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform 5, 150–163.[CrossRef] [Google Scholar]
  19. Li, L., Victoria, J., Kapoor, A., Naeem, A., Shaukat, S., Sharif, S., Alam, M. M., Angez, M., Zaidi, S. Z. & Delwart, E.(2009). Genomic characterization of novel human parechovirus type. Emerg Infect Dis 15, 288–291.[CrossRef] [Google Scholar]
  20. Lukashev, A. N.(2005). Role of recombination in evolution of enteroviruses. Rev Med Virol 15, 157–167.[CrossRef] [Google Scholar]
  21. Lukashev, A. N., Lashkevich, V. A., Ivanova, O. E., Koroleva, G. A., Hinkkanen, A. E. & Ilonen, J.(2003). Recombination in circulating enteroviruses. J Virol 77, 10423–10431.[CrossRef] [Google Scholar]
  22. Mizuta, K., Abiko, C., Murata, T., Matsuzaki, Y., Itagaki, T., Sanjoh, K., Sakamoto, M., Hongo, S., Murayama, S. & Hayasaka, K.(2005). Frequent importation of enterovirus 71 from surrounding countries into the local community of Yamagata, Japan, between 1998 and 2003. J Clin Microbiol 43, 6171–6175.[CrossRef] [Google Scholar]
  23. Munemura, T., Saikusa, M., Kawakami, C., Shimizu, H., Oseto, M., Hagiwara, A., Kimura, H. & Miyamura, T.(2003). Genetic diversity of enterovirus 71 isolated from cases of hand, foot and mouth disease in Yokohama City between 1982 and 2000. Arch Virol 148, 253–263.[CrossRef] [Google Scholar]
  24. Nateri, A. S., Hughes, P. J. & Stanway, G.(2000). In vivo and in vitro identification of structural and sequence elements of the human parechovirus 5′ untranslated region required for internal initiation. J Virol 74, 6269–6277.[CrossRef] [Google Scholar]
  25. Oberste, M. S., Maher, K. & Pallansch, M.(1998). Complete sequence of echovirus 23 and its relationship to echovirus 22 and other human enteroviruses. Virus Res 56, 217–223.[CrossRef] [Google Scholar]
  26. Oberste, M. S., Maher, K. & Pallansch, M. A.(2004a). Evidence for frequent recombination within species Human enterovirus B based on complete genomic sequences of all thirty-seven serotypes. J Virol 78, 855–867.[CrossRef] [Google Scholar]
  27. Oberste, M. S., Michele, S. M., Maher, K., Schnurr, D., Cisterna, D., Junttila, N., Uddin, M., Chomel, J. J., Lau, C. S. & other authors(2004b). Molecular identification and characterization of two proposed new enterovirus serotypes, EV74 and EV75. J Gen Virol 85, 3205–3212.[CrossRef] [Google Scholar]
  28. Oberste, M. S., Penaranda, S. & Pallansch, M. A.(2004c). RNA recombination plays a major role in genomic change during circulation of coxsackie B viruses. J Virol 78, 2948–2955.[CrossRef] [Google Scholar]
  29. Santti, J., Hyypia, T., Kinnunen, L. & Salminen, M.(1999). Evidence of recombination among enteroviruses. J Virol 73, 8741–8749. [Google Scholar]
  30. Savolainen, C., Hovi, T. & Mulders, M. N.(2001). Molecular epidemiology of echovirus 30 in Europe: succession of dominant sublineages within a single major genotype. Arch Virol 146, 521–537.[CrossRef] [Google Scholar]
  31. Simmonds, P.(2006). Recombination and selection in the evolution of picornaviruses and other mammalian positive-stranded RNA viruses. J Virol 80, 11124–11140.[CrossRef] [Google Scholar]
  32. Simmonds, P. & Smith, D. B.(1999). Structural constraints on RNA virus evolution. J Virol 73, 5787–5794. [Google Scholar]
  33. Simmonds, P. & Welch, J.(2006). Frequency and dynamics of recombination within different species of human enteroviruses. J Virol 80, 483–493.[CrossRef] [Google Scholar]
  34. Stanway, G., Kalkkinen, N., Roivainen, M., Ghazi, F., Khan, M., Smyth, M., Meurman, O. & Hyypia, T.(1994). Molecular and biological characteristics of echovirus 22, a representative of a new picornavirus group. J Virol 68, 8232–8238. [Google Scholar]
  35. Stanway, G., Joki-Korpela, P. & Hyypia, T.(2000). Human parechoviruses – biology and clinical significance. Rev Med Virol 10, 57–69.[CrossRef] [Google Scholar]
  36. Tapia, G., Cinek, O., Witso, E., Kulich, M., Rasmussen, T., Grinde, B. & Ronningen, K. S.(2008). Longitudinal observation of parechovirus in stool samples from Norwegian infants. J Med Virol 80, 1835–1842.[CrossRef] [Google Scholar]
  37. Tosh, C., Hemadri, D. & Sanyal, A.(2002). Evidence of recombination in the capsid-coding region of type A foot-and-mouth disease virus. J Gen Virol 83, 2455–2460. [Google Scholar]
  38. van der Hoek, L., Pyrc, K., Jebbink, M. F., Vermeulen-Oost, W., Berkhout, R. J., Wolthers, K. C., Wertheim-Van Dillen, P. M., Kaandorp, J., Spaargaren, J. & Berkhout, B.(2004). Identification of a new human coronavirus. Nat Med 10, 368–373.[CrossRef] [Google Scholar]
  39. van der Sanden, S., de Bruin, E., Vennema, H., Swanink, C., Koopmans, M. & van der Avoort, H.(2008). Prevalence of human parechovirus in The Netherlands in 2000 to 2007. J Clin Microbiol 46, 2884–2889.[CrossRef] [Google Scholar]
  40. Verboon-Maciolek, M. A., Groenendaal, F., Hahn, C. D., Hellmann, J., van Loon, A. M., Boivin, G. & de Vries, L. S.(2008). Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol 64, 266–273.[CrossRef] [Google Scholar]
  41. Wakatsuki, K., Kawamoto, D., Hiwaki, H., Watanabe, K. & Yoshida, H.(2008). Identification and characterization of two strains of human parechovirus 4 isolated from two clinical cases in Fukuoka City, Japan. J Clin Microbiol 46, 3144–3146.[CrossRef] [Google Scholar]
  42. Wang, J. R., Tuan, Y. C., Tsai, H. P., Yan, J. J., Liu, C. C. & Su, I. J.(2002). Change of major genotype of enterovirus 71 in outbreaks of hand-foot-and-mouth disease in Taiwan between 1998 and 2000. J Clin Microbiol 40, 10–15.[CrossRef] [Google Scholar]
  43. Watanabe, K., Oie, M., Higuchi, M., Nishikawa, M. & Fujii, M.(2007). Isolation and characterization of novel human parechovirus from clinical samples. Emerg Infect Dis 13, 889–895.[CrossRef] [Google Scholar]
  44. Williams, C. H., Panayiotou, M., Girling, G. D., Peard, C. I., Oikarinen, S., Hyoty, H. & Stanway, G.(2009). Evolution and conservation in human parechovirus genomes. J Gen Virol 90, 1702–1712.[CrossRef] [Google Scholar]
  45. Wolthers, K. C., Benschop, K. S., Schinkel, J., Molenkamp, R., Bergevoet, R. M., Spijkerman, I. J., Kraakman, H. C. & Pajkrt, D.(2008). Human parechoviruses as an important viral cause of sepsislike illness and meningitis in young children. Clin Infect Dis 47, 358–363.[CrossRef] [Google Scholar]
  46. Zoll, J., Galama, J. M. & van Kuppeveld, F. J.(2009). Identification of potential recombination breakpoints in human parechoviruses. J Virol 83, 3379–3383.[CrossRef] [Google Scholar]

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error