Skip to main content

Advertisement

Log in

The origin of porcine endogenous retroviruses (PERVs)

  • Review
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and they produce viral particles that are able to infect human cells and therefore pose a special risk for xenotransplantation. In contrast to other pig microorganisms that also pose a risk, such as porcine cytomegalovirus and hepatitis E virus, PERVs cannot be eliminated from pigs by vaccines, antiviral drugs, early weaning, or embryo transfer. Since PERVs are relevant for xenotransplantation, their biology and origin are of great interest. Recent studies have shown that PERVs are the result of a transspecies transmission of precursor retroviruses from different animals and further evolution in the pig genome. PERVs acquired different long terminal repeats (LTRs), and recombination took place. In parallel, it has been shown that the activity of the LTRs and recombination in the envelope are important for the transmissibility and pathogenesis of PERVs. Transspecies transmission of retroviruses is common, a well-known example being the transmission of precursor retroviruses from non-human primates to humans, resulting in human immunodeficiency virus (HIV). Here, recent findings concerning the origin of PERVs, their LTRs, and recombination events that occurred during evolution are reviewed and compared with other findings regarding transspecies transmission of retroviruses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Denner J, Tönjes RR (2012) Infection barriers to successful xenotransplantation focusing on porcine endogenous retroviruses. Clin Microbiol Rev 25(2):318–343

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Coffin JM, Hughes SH, Varmus HE (1997) Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  3. Denner J, Mueller NJ (2015) Preventing transfer of infectious agents. Int J Surg 23(Pt B):306–311

    PubMed  PubMed Central  Google Scholar 

  4. Fishman JA (2018) Infectious disease risks in xenotransplantation. Am J Transplant 18(8):1857–1864

    PubMed  Google Scholar 

  5. Denner J, Längin M, Reichart B, Krüger L, Fiebig U, Mokelke M, Radan J, Mayr T, Milusev A, Luther F, Sorvillo N, Rieben R, Brenner P, Walz C, Wolf E, Roshani B, Stahl-Hennig C, Abicht J-M (2020) Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival. Sci Rep. https://doi.org/10.1101/2020.04.07.029702 ((preprint: bioRxiv))

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yamada K, Tasaki M, Sekijima M, Wilkinson RA, Villani V, Moran SG, Cormack TA, Hanekamp IM, Hawley RJ, Arn JS, Fishman JA, Shimizu A, Sachs DH (2014) Porcine cytomegalovirus infection is associated with early rejection of kidney grafts in a pig to baboon xenotransplantation model. Transplantation 98(4):411–418

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Denner J (2020) Sensitive detection systems for infectious agents in xenotransplantation. Xenotransplantation 18:e12594

    Google Scholar 

  8. Niu D, Wei HJ, Lin L, George H, Wang T, Lee IH, Zhao HY, Wang Y, Kan Y, Shrock E, Lesha E, Wang G, Luo Y, Qing Y, Jiao D, Zhao H, Zhou X, Wang S, Wei H, Güell M, Church GM, Yang L (2017) Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science 357(6357):1303–1307

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Scobie L, Denner J, Schuurman HJ (2017) Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9, editorial commentary. Xenotransplantation 24(6):e12363

    Google Scholar 

  10. Garkavenko O, Dieckhoff B, Wynyard S, Denner J, Elliott RB, Tan PL, Croxson MC (2008) Absence of transmission of potentially xenotic viruses in a prospective pig to primate islet xenotransplantation study. J Med Virol. 80(11):2046–2052

    CAS  PubMed  Google Scholar 

  11. Denner J, Tönjes RR, Takeuchi Y, Fishman J, Scobie L (2016) First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—chapter 5: recipient monitoring and response plan for preventing disease transmission. Xenotransplantation 23(1):53–59

    PubMed  Google Scholar 

  12. Denner J (2018) Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? Retrovirology 15(1):28

    PubMed  PubMed Central  Google Scholar 

  13. Wynyard S, Nathu D, Garkavenko O, Denner J, Elliott R (2014) Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. Xenotransplantation 21(4):309–323

    PubMed  Google Scholar 

  14. Morozov VA, Wynyard S, Matsumoto S, Abalovich A, Denner J, Elliott R (2017) No PERV transmission during a clinical trial of pig islet cell transplantation. Virus Res. 227:34–40

    CAS  PubMed  Google Scholar 

  15. Denner J (2016) How active are porcine endogenous retroviruses (PERVs)? Viruses 8(8):215

    PubMed Central  Google Scholar 

  16. Cooper DKC (2020) Introduction: the present status of xenotransplantation research. Methods Mol Biol. 2110:1–25

    CAS  PubMed  Google Scholar 

  17. Längin M, Mayr T, Reichart B, Michel S, Buchholz S, Guethoff S, Dashkevich A, Baehr A, Egerer S, Bauer A, Mihalj M, Panelli A, Issl L, Ying J, Fresch AK, Buttgereit I, Mokelke M, Radan J, Werner F, Lutzmann I, Steen S, Sjöberg T, Paskevicius A, Qiuming L, Sfriso R, Rieben R, Dahlhoff M, Kessler B, Kemter E, Kurome M, Zakhartchenko V, Klett K, Hinkel R, Kupatt C, Falkenau A, Reu S, Ellgass R, Herzog R, Binder U, Wich G, Skerra A, Ayares D, Kind A, Schönmann U, Kaup FJ, Hagl C, Wolf E, Klymiuk N, Brenner P, Abicht JM (2018) Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 564(7736):430–433

  18. Fishman JA (2020) Prevention of infection in xenotransplantation: Designated pathogen-free swine in the safety equation. Xenotransplantation 3:e12595

    Google Scholar 

  19. Ericsson TA, Takeuchi Y, Templin C, Quinn G, Farhadian SF, Wood JC, Oldmixon BA, Suling KM, Ishii JK, Kitagawa Y, Miyazawa T, Salomon DR, Weiss RA, Patience C (2003) Identification of receptors for pig endogenous retrovirus. Proc Natl Acad Sci USA 100(11):6759–6764

    CAS  PubMed  Google Scholar 

  20. Chen Y, Chen X, Duan X, Cui J (2020) Ancient origin and complex evolution of porcine endogenous retroviruses. Biosaf Health 2(3):142–151. https://doi.org/10.1016/j.bsheal.2020.03.003

    Article  Google Scholar 

  21. Niebert M, Kurth R, Tönjes RR (2003) Retroviral safety: analyses of phylogeny, prevalence and polymorphisms of porcine endogenous retroviruses. Ann Transplant 8(3):56–64

    CAS  PubMed  Google Scholar 

  22. Denner J, Specke V, Thiesen U, Karlas A, Kurth R (2003) Genetic alterations of the long terminal repeat of an ecotropic porcine endogenous retrovirus during passage in human cells. Virology 314(1):125–133

    CAS  PubMed  Google Scholar 

  23. Wilson CA, Laeeq S, Ritzhaupt A, Colon-Moran W, Yoshimura FK (2003) Sequence analysis of porcine endogenous retrovirus long terminal repeats and identification of transcriptional regulatory regions. J Virol 77(1):142–149

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Fiebig U, Fischer K, Bähr A, Runge C, Schnieke A, Wolf E, Denner J (2018) Porcine endogenous retroviruses: Quantification of the copy number in cell lines, pig breeds, and organs. Xenotransplantation 25(4):e12445

    PubMed  Google Scholar 

  25. Krüger L, Stillfried M, Prinz C, Schröder V, Neubert LK, Denner J (2020) Copy number and prevalence of porcine endogenous retroviruses (PERVs) in German wild boars. Viruses 12(4):419

    PubMed Central  Google Scholar 

  26. Mazurek U, Kimsa MC, Strzalka-Mrozik B, Kimsa MW, Adamska J, Lipinski D (2013) Quantitative analysis of porcine endogenous retroviruses in different organs of transgenic pigs generated for xenotransplantation. Curr Microbiol 64:505–514

    Google Scholar 

  27. Mourad NI, Crossan C, Cruikshank V, Scobie L, Gianello P (2017) Characterization of porcine endogenous retrovirus expression in neonatal and adult pig pancreatic islets. Xenotransplantation 24(4):e12311

    Google Scholar 

  28. Benveniste RE, Todaro GJ (1975) Evolution of type C viral genes: preservation of ancestral murine type C viral sequences in pig cellular DNA. Proc Natl Acad Sci USA 72(10):4090–4094

    CAS  PubMed  Google Scholar 

  29. Tönjes RR, Niebert M (2003) Relative age of proviral porcine endogenous retrovirus sequences in Sus scrofa based on the molecular clock hypothesis. J Virol 77:12363–12368

    PubMed  PubMed Central  Google Scholar 

  30. Sharp PM, Bailes E, Robertson DL, Gao F, Hahn BH (1999) Origins and evolution of AIDS viruses. Biol Bull 196(3):338–342

    CAS  PubMed  Google Scholar 

  31. Patience C, Switzer WM, Takeuchi Y, Griffiths DJ, Goward ME, Heneine W, Stoye JP, Weiss RA (2001) Multiple groups of novel retroviral genomes in pigs and related species. J Virol 75:2771–2775

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Wilson CA, Wong S, VanBrocklin M, Federspiel MJ (2000) Extended analysis of the in vitro tropism of porcine endogenous retrovirus. J Virol 74(1):49–56

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Karlas A, Irgang M, Votteler J, Specke V, Ozel M, Kurth R, Denner J (2010) Characterisation of a human cell-adapted porcine endogenous retrovirus PERV-A/C. Ann Transplant 15(2):45–54

    CAS  PubMed  Google Scholar 

  34. Scheef G, Fischer N, Krach U, Tönjes RR (2001) The number of a U3 repeat box acting as an enhancer in long terminal repeats of polytropic replication-competent porcine endogenous retroviruses dynamically fluctuates during serial virus passages in human cells. J Virol 75(15):6933–6940

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Harrison I, Takeuchi Y, Bartosch B, Stoye JP (2004) Determinants of high titer in recombinant porcine endogenous retroviruses. J Virol 78(24):13871–13879

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Krüger L, Kristiansen Y, Reuber E, Möller L, Laue M, Reimer C, Denner JA (2019) Comprehensive strategy for screening for xenotransplantation-relevant viruses in a second isolated population of Göttingen Minipigs. Viruses 12(1):38

    PubMed Central  Google Scholar 

  37. Scobie L, Taylor S, Wood JC, Suling KM, Quinn G, Meikle S, Patience C, Schuurman HJ, Onions DE (2004) Absence of replication-competent human-tropic porcine endogenous retroviruses in the germ line DNA of inbred miniature Swine. J Virol 78(5):2502–2509

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kaulitz D, Mihica D, Adlhoch C, Semaan M, Denner J (2013) Improved pig donor screening including newly identified variants of porcine endogenous retrovirus-C (PERV-C). Arch Virol 158(2):341–348

    CAS  PubMed  Google Scholar 

  39. Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw GM, Sharp PM, Hahn BH (1999) Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397(6718):436–441

    CAS  PubMed  Google Scholar 

  40. Keele BF, Jones JH, Terio KA, Estes JD, Rudicell RS, Wilson ML, Li Y, Learn GH, Beasley TM, Schumacher-Stankey J, Wroblewski E, Mosser A, Raphael J, Kamenya S, Lonsdorf EV, Travis DA, Mlengeya T, Kinsel MJ, Else JG, Silvestri G, Goodall J, Sharp PM, Shaw GM, Pusey AE, Hahn BH (2009) Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz. Nature 460(7254):515–519

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bailes E, Gao F, Bibollet-Ruche F, Courgnaud V, Peeters M, Marx PA, Hahn BH, Sharp PM (2003) Hybrid origin of SIV in chimpanzees. Science 300(5626):1713

    CAS  PubMed  Google Scholar 

  42. Leitner T, Dazza MC, Ekwalanga M, Apetrei C, Saragosti S (2007) Sequence diversity among chimpanzee simian immunodeficiency viruses (SIVcpz) suggests that SIVcpzPts was derived from SIVcpzPtt through additional recombination events. AIDS Res Hum Retroviruses 23(9):1114–1118

    CAS  PubMed  Google Scholar 

  43. Gao F, Yue L, Robertson DL, Hill SC, Hui H, Biggar RJ, Neequaye AE, Whelan TM, Ho DD, Shaw GM (1994) Genetic diversity of human immunodeficiency virus type 2: evidence for distinct sequence subtypes with differences in virus biology. J Virol 68(11):7433–7447

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kestler H, Kodama T, Ringler D, Marthas M, Pedersen N, Lackner A, Regier D, Sehgal P, Daniel M, King N (1990) Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus. Science 248(4959):1109–1112

    CAS  PubMed  Google Scholar 

  45. Denner J, Young PR (2013) Koala retroviruses: characterization and impact on the life of koalas. Retrovirology. 10:108

    PubMed  PubMed Central  Google Scholar 

  46. Denner J (2016) Transspecies transmission of gammaretroviruses and the origin of the gibbon ape leukaemia virus (GaLV) and the koala retrovirus (KoRV). Viruses 8(12):336

    PubMed Central  Google Scholar 

  47. Denner J (2007) Transspecies transmissions of retroviruses: new cases. Virology 369(2):229–233

    CAS  PubMed  Google Scholar 

  48. Shimode S, Nakagawa S, Miyazawa T (2015) Multiple invasions of an infectious retrovirus in cat genomes. Sci Rep 5:8164

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Franklin SP, Troyer JL, Terwee JA, Lyren LM, Boyce WM, Riley SP, Roelke ME, Crooks KR, Vandewoude S (2007) Frequent transmission of immunodeficiency viruses among bobcats and pumas. J Virol 81(20):10961–10969

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Koralnik IJ, Boeri E, Saxinger WC, Monico AL, Fullen J, Gessain A, Guo HG, Gallo RC, Markham P, Kalyanaraman V (1994) Phylogenetic associations of human and simian T-cell leukemia/lymphotropic virus type I strains: evidence for interspecies transmission. J Virol 68(4):2693–2707

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Voevodin A, Samilchuk E, Schätzl H, Boeri E, Franchini G (1996) Interspecies transmission of macaque simian T-cell leukemia/lymphoma virus type 1 in baboons resulted in an outbreak of malignant lymphoma. J Virol 70(3):1633–1639

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wolfe ND, Heneine W, Carr JK, Garcia AD, Shanmugam V, Tamoufe U, Torimiro JN, Prosser AT, Lebreton M, Mpoudi-Ngole E, McCutchan FE, Birx DL, Folks TM, Burke DS, Switzer WM (2005) Emergence of unique primate T-lymphotropic viruses among central African bushmeat hunters. Proc Natl Acad Sci USA 102(22):7994–7999

    CAS  PubMed  Google Scholar 

  53. Gessain A, Rua R, Betsem E, Turpin J, Mahieux R (2013) HTLV-3/4 and simian foamy retroviruses in humans: discovery, epidemiology, cross-species transmission and molecular virology. Virology 435(1):187–199

    CAS  PubMed  Google Scholar 

  54. Pinto-Santini DM, Stenbak CR, Linial ML (2017) Foamy virus zoonotic infections. Retrovirology 14(1):55

    PubMed  PubMed Central  Google Scholar 

  55. Heneine W, Switzer WM, Sandstrom P, Brown J, Vedapuri S, Schable CA, Khan AS, Lerche NW, Schweizer M, Neumann-Haefelin D, Chapman LE, Folks TM (1998) Identification of a human population infected with simian foamy viruses. Nat Med 4(4):403–407

    CAS  PubMed  Google Scholar 

  56. Shah C, Huder JB, Böni J, Schönmann M, Mühlherr J, Lutz H, Schüpbach J (2004) Direct evidence for natural transmission of small-ruminant lentiviruses of subtype A4 from goats to sheep and vice versa. J Virol 78(14):7518–7522

    CAS  PubMed  PubMed Central  Google Scholar 

  57. van der Kuyl AC, Dekker JT, Goudsmit J (1999) Discovery of a new endogenous type C retrovirus (FcEV) in cats: evidence for RD-114 being an FcEVGag-Pol/baboon endogenous virus BaEVEnv recombinant. J Virol 73(10):7994–8002

    PubMed  PubMed Central  Google Scholar 

  58. Benveniste RE, Todaro GJ (1977) Evolution of primate oncornaviruses: an endogenous virus from langurs (Presbytis spp.) with related virogene sequences in other Old World monkeys. Proc Natl Acad Sci USA 74(10):4557–4561

    CAS  PubMed  Google Scholar 

  59. Hanger JJ, Bromham LD, McKee JJ, O’Brien TM, Robinson WF (2000) The nucleotide sequence of koala (Phascolarctos cinereus) retrovirus: a novel type C endogenous virus related to Gibbon ape leukemia virus. J Virol 74(9):4264–4272

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The studies performed in my laboratory were supported by the German Research Foundation, TRR127.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joachim Denner.

Ethics declarations

Conflict of interest

The author declares no conflict of interest.

Additional information

Handling Editor: Zhongjie Shi.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Denner, J. The origin of porcine endogenous retroviruses (PERVs). Arch Virol 166, 1007–1013 (2021). https://doi.org/10.1007/s00705-020-04925-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-020-04925-8

Navigation