1887

Journal of General Virology header logo

Volume 93, Issue 11

Evolution of the hepatitis E virus hypervariable region Open Access

Abstract

The presence of a hypervariable (HVR) region within the genome of hepatitis E virus (HEV) remains unexplained. Previous studies have described the HVR as a proline-rich spacer between flanking functional domains of the ORF1 polyprotein. Others have proposed that the region has no function, that it reflects a hypermutable region of the virus genome, that it is derived from the insertion and evolution of host sequences or that it is subject to positive selection. This study attempts to differentiate between these explanations by documenting the evolutionary processes occurring within the HVR. We have measured the diversity of HVR sequences within acutely infected individuals or amongst sequences derived from epidemiologically linked samples and, surprisingly, find relative homogeneity amongst these datasets. We found no evidence of positive selection for amino acid substitution in the HVR. Through an analysis of published sequences, we conclude that the range of HVR diversity observed within virus genotypes can be explained by the accumulation of substitutions and, to a much lesser extent, through deletions or duplications of this region. All published HVR amino acid sequences display a relative overabundance of proline and serine residues that cannot be explained by a local bias towards cytosine in this part of the genome. Although all published HVRs contain one or more SH3-binding PxxP motifs, this motif does not occur more frequently than would be expected from the proportion of proline residues in these sequences. Taken together, these observations are consistent with the hypothesis that the HVR has a structural role that is dependent upon length and amino acid composition, rather than a specific sequence.

  • Received:
  • Accepted:
  • Published Online:
© 2012 SGM
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.045351-0
2012-11-01
2024-04-26
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/11/2408.html?itemId=/content/journal/jgv/10.1099/vir.0.045351-0&mimeType=html&fmt=ahah

References

  1. Ahmad I., Holla R. P., Jameel S. 2011; Molecular virology of hepatitis E virus. Virus Res 161:47–58 [View Article][PubMed]
     [Google Scholar]
  2. Arankalle V. A., Paranjape S., Emerson S. U., Purcell R. H., Walimbe A. M. 1999; Phylogenetic analysis of hepatitis E virus isolates from India (1976–1993). J Gen Virol 80:1691–1700[PubMed]
     [Google Scholar]
  3. Batts W., Yun S., Hedrick R., Winton J. 2011; A novel member of the family Hepeviridae from cutthroat trout (Oncorhynchus clarkii). Virus Res 158:116–123 [View Article][PubMed]
     [Google Scholar]
  4. Berens S. J., Brayton K. A., Molloy J. B., Bock R. E., Lew A. E., McElwain T. F. 2005; Merozoite surface antigen 2 proteins of Babesia bovis vaccine breakthrough isolates contain a unique hypervariable region composed of degenerate repeats. Infect Immun 73:7180–7189 [View Article][PubMed]
     [Google Scholar]
  5. Bouquet J., Cheval J., Rogée S., Pavio N., Eloit M. 2012; Identical consensus sequence and conserved genomic polymorphism of hepatitis E virus during controlled interspecies transmission. J Virol 86:6238–6245 [View Article][PubMed]
     [Google Scholar]
  6. Bryan J. P., Tsarev S. A., Iqbal M., Ticehurst J., Emerson S., Ahmed A., Duncan J., Rafiqui A. R., Malik I. A. other authors 1994; Epidemic hepatitis E in Pakistan: patterns of serologic response and evidence that antibody to hepatitis E virus protects against disease. J Infect Dis 170:517–521 [View Article][PubMed]
     [Google Scholar]
  7. Erker J. C., Desai S. M., Schlauder G. G., Dawson G. J., Mushahwar I. K. 1999; A hepatitis E virus variant from the United States: molecular characterization and transmission in cynomolgus macaques. J Gen Virol 80:681–690[PubMed]
     [Google Scholar]
  8. Gouvea V., Snellings N., Popek M. J., Longer C. F., Innis B. L. 1998; Hepatitis E virus: complete genome sequence and phylogenetic analysis of a Nepali isolate. Virus Res 57:21–26 [View Article][PubMed]
     [Google Scholar]
  9. Huang F. F., Sun Z. F., Emerson S. U., Purcell R. H., Shivaprasad H. L., Pierson F. W., Toth T. E., Meng X. J. 2004; Determination and analysis of the complete genomic sequence of avian hepatitis E virus (avian HEV) and attempts to infect rhesus monkeys with avian HEV. J Gen Virol 85:1609–1618 [View Article][PubMed]
     [Google Scholar]
  10. Johne R., Heckel G., Plenge-Bönig A., Kindler E., Maresch C., Reetz J., Schielke A., Ulrich R. G. 2010; Novel hepatitis E virus genotype in Norway rats, Germany. Emerg Infect Dis 16:1452–1455 [View Article][PubMed]
     [Google Scholar]
  11. Kamar N., Bendall R., Legrand-Abravanel F., Xia N. S., Ijaz S., Izopet J., Dalton H. R. 2012; Hepatitis E. Lancet 379:2477–2488 [View Article][PubMed]
     [Google Scholar]
  12. Kay B. K., Williamson M. P., Sudol M. 2000; The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J 14:231–241[PubMed]
     [Google Scholar]
  13. Kayman S. C., Park H., Saxon M., Pinter A. 1999; The hypervariable domain of the murine leukemia virus surface protein tolerates large insertions and deletions, enabling development of a retroviral particle display system. J Virol 73:1802–1808[PubMed]
     [Google Scholar]
  14. Koonin E. V., Gorbalenya A. E., Purdy M. A., Rozanov M. N., Reyes G. R., Bradley D. W. 1992; Computer-assisted assignment of functional domains in the nonstructural polyprotein of hepatitis E virus: delineation of an additional group of positive-strand RNA plant and animal viruses. Proc Natl Acad Sci U S A 89:8259–8263 [View Article][PubMed]
     [Google Scholar]
  15. Korkaya H., Jameel S., Gupta D., Tyagi S., Kumar R., Zafrullah M., Mazumdar M., Lal S. K., Xiaofang L. other authors 2001; The ORF3 protein of hepatitis E virus binds to Src homology 3 domains and activates MAPK. J Biol Chem 276:42389–42400 [View Article][PubMed]
     [Google Scholar]
  16. LeRoith T., Berens S. J., Brayton K. A., Hines S. A., Brown W. C., Norimine J., McElwain T. F. 2006; The Babesia bovis merozoite surface antigen 1 hypervariable region induces surface-reactive antibodies that block merozoite invasion. Infect Immun 74:3663–3667 [View Article][PubMed]
     [Google Scholar]
  17. Lorenzo F. R., Tanaka T., Takahashi H., Ichiyama K., Hoshino Y., Yamada K., Inoue J., Takahashi M., Okamoto H. 2008; Mutational events during the primary propagation and consecutive passages of hepatitis E virus strain JE03-1760F in cell culture. Virus Res 137:86–96 [View Article][PubMed]
     [Google Scholar]
  18. Matsubayashi K., Kang J. H., Sakata H., Takahashi K., Shindo M., Kato M., Sato S., Kato T., Nishimori H. other authors 2008; A case of transfusion-transmitted hepatitis E caused by blood from a donor infected with hepatitis E virus via zoonotic food-borne route. Transfusion 48:1368–1375 [View Article][PubMed]
     [Google Scholar]
  19. Meng X. J., Anderson D. A., Arankalle V. A., Emerson S. U., Harrison T. J., Jameel S., Okamoto H. 2012; Family Hepeviridae . In Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses pp. 991–998 Edited by King A. M. Q., Adams M. J., Carstens E. B., Lefkowitz E. J. London: Elsevier/Academic Press;
     [Google Scholar]
  20. Miyashita K., Kang J. H., Saga A., Takahashi K., Shimamura T., Yasumoto A., Fukushima H., Sogabe S., Konishi K. other authors 2012; Three cases of acute or fulminant hepatitis E caused by ingestion of pork meat and entrails in Hokkaido, Japan: zoonotic food-borne transmission of hepatitis E virus and public health concerns. Hepatol Res 42:870–878[PubMed] [CrossRef]
     [Google Scholar]
  21. Neuvonen M., Kazlauskas A., Martikainen M., Hinkkanen A., Ahola T., Saksela K. 2011; SH3 domain-mediated recruitment of host cell amphiphysins by alphavirus nsP3 promotes viral RNA replication. PLoS Pathog 7:e1002383 [View Article][PubMed]
     [Google Scholar]
  22. Nguyen H. T., Torian U., Faulk K., Mather K., Engle R. E., Thompson E., Bonkovsky H. L., Emerson S. U. 2012; A naturally occurring human/hepatitis E recombinant virus predominates in serum but not in faeces of a chronic hepatitis E patient and has a growth advantage in cell culture. J Gen Virol 93:526–530 [View Article][PubMed]
     [Google Scholar]
  23. Osterman A., Vizoso Pinto M. G., Haase R., Nitschko H., Jäger S., Sander M., Motz M., Mohn U., Baiker A. 2012; Systematic screening for novel, serologically reactive hepatitis E virus epitopes. Virol J 9:28 [View Article][PubMed]
     [Google Scholar]
  24. Ott D., Friedrich R., Rein A. 1990; Sequence analysis of amphotropic and 10A1 murine leukemia viruses: close relationship to mink cell focus-inducing viruses. J Virol 64:757–766[PubMed]
     [Google Scholar]
  25. Pond S. L., Frost S. D., Muse S. V. 2005; HyPhy: hypothesis testing using phylogenies. Bioinformatics 21:676–679 [View Article][PubMed]
     [Google Scholar]
  26. Pudupakam R. S., Huang Y. W., Opriessnig T., Halbur P. G., Pierson F. W., Meng X. J. 2009; Deletions of the hypervariable region (HVR) in open reading frame 1 of hepatitis E virus do not abolish virus infectivity: evidence for attenuation of HVR deletion mutants in vivo. J Virol 83:384–395 [View Article][PubMed]
     [Google Scholar]
  27. Pudupakam R. S., Kenney S. P., Córdoba L., Huang Y. W., Dryman B. A., Leroith T., Pierson F. W., Meng X. J. 2011; Mutational analysis of the hypervariable region of hepatitis e virus reveals its involvement in the efficiency of viral RNA replication. J Virol 85:10031–10040 [View Article][PubMed]
     [Google Scholar]
  28. Purdy M. A., Lara J., Khudyakov Y. E. 2012; The hepatitis E virus polyproline region is involved in viral adaptation. PLoS ONE 7:e35974 [View Article][PubMed]
     [Google Scholar]
  29. Shrestha M. P., Scott R. M., Joshi D. M., Mammen M. P. Jr, Thapa G. B., Thapa N., Myint K. S., Fourneau M., Kuschner R. A. other authors 2007; Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 356:895–903 [View Article][PubMed]
     [Google Scholar]
  30. Shukla P., Nguyen H. T., Torian U., Engle R. E., Faulk K., Dalton H. R., Bendall R. P., Keane F. E., Purcell R. H., Emerson S. U. 2011; Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant. Proc Natl Acad Sci U S A 108:2438–2443 [View Article][PubMed]
     [Google Scholar]
  31. Simmonds P. 2012; sse: a nucleotide and amino acid sequence analysis platform. BMC Res Notes 5:50 [View Article][PubMed]
     [Google Scholar]
  32. Suppiah S., Mousa H. A., Tzeng W. P., Matthews J. D., Frey T. K. 2012; Binding of cellular p32 protein to the rubella virus P150 replicase protein via PxxPxR motifs. J Gen Virol 93:807–816 [View Article][PubMed]
     [Google Scholar]
  33. Takahashi K., Kitajima N., Abe N., Mishiro S. 2004; Complete or near-complete nucleotide sequences of hepatitis E virus genome recovered from a wild boar, a deer, and four patients who ate the deer. Virology 330:501–505 [View Article][PubMed]
     [Google Scholar]
  34. Takahashi M., Tanaka T., Azuma M., Kusano E., Aikawa T., Shibayama T., Yazaki Y., Mizuo H., Inoue J., Okamoto H. 2007; Prolonged fecal shedding of hepatitis E virus (HEV) during sporadic acute hepatitis E: evaluation of infectivity of HEV in fecal specimens in a cell culture system. J Clin Microbiol 45:3671–3679 [View Article][PubMed]
     [Google Scholar]
  35. Tamura K., Dudley J., Nei M., Kumar S. 2007; mega4: Molecular Evolutionary Genetics Analysis (mega) software version 4.0. Mol Biol Evol 24:1596–1599 [View Article][PubMed]
     [Google Scholar]
  36. Tsarev S. A., Emerson S. U., Reyes G. R., Tsareva T. S., Legters L. J., Malik I. A., Iqbal M., Purcell R. H. 1992; Characterization of a prototype strain of hepatitis E virus. Proc Natl Acad Sci U S A 89:559–563 [View Article][PubMed]
     [Google Scholar]
  37. Williamson M. P. 1994; The structure and function of proline-rich regions in proteins. Biochem J 297:249–260[PubMed]
     [Google Scholar]
  38. Wu B. W., Cannon P. M., Gordon E. M., Hall F. L., Anderson W. F. 1998; Characterization of the proline-rich region of murine leukemia virus envelope protein. J Virol 72:5383–5391[PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.045351-0
Loading
Evolution of the hepatitis E virus hypervariable region
J. Gen. Virol. 93, 2408 (2012); https://doi.org/10.1099/vir.0.045351-0
/content/journal/jgv/10.1099/vir.0.045351-0
/content/journal/jgv/10.1099/vir.0.045351-0
Loading

Data & Media loading...

Most cited 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