Skip to main content
SpringerLink
Log in

Molecular Cloning and Functional Characterization of Infectious PERV and Development of Diagnostic Tests

  • Chapter
Book cover Xeno-transplantation

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 278))

Abstract

Pigs are the donor animals of choice for xenotransplantation (XTx) and xenogeneic cell therapy measurements Most known porcine athogens can be controlled by conventional means like vaccination, medication or specific pathogen-free breeding conditions. As pigs haveco-evolved very closely with humans for a few millennia it is not very likely that even asymptomatic pathogens have escaped attention. Porcine endogenous retroviruses (PERV) are different from conventional pathogens as they are chromosomally fixed in every cell of the animal, hence PERV cannot be easily controlled. While PERV show no phenotype in the porcine host, recent data demonstrate that some polytropic proviruses can be activated by external stimuli and that those can productively infect human cells in vitro. In evaluation of the retrovirological safety of XTx, we determined the number of replication-competent PERV to be limited and to exhibit a heterogeneous distribution, therefore suggesting that they could be removed by conventional breeding. The transcriptional regulation of some PERV due to repetitive elements in their long terminal repeats enables their adaptation to new host cells. The diagnostic tools available, based on immunological and polymerase chain reaction techniques, were shown to be sensitive in both the animal and in vitro, but must still show their potential in human XTx recipients, where they are confronted with very low antigen expression and the phenomenon of microchimerism.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Akiyoshi DE, Denaro M, Zhu H, Greenstein JL, Banerjee PT and Fishman JA (1998) Identification of a full-length cDNA for an endogenous retrovirus of miniature swine. J Virol 72:4503–4507

    PubMed  CAS  Google Scholar 

  • Bach FH, Ivinson AJ and Weeramantry HE (2001) Ethical and legal issues in technology: xenotransplantation. Am J Law Med 27:283–300

    PubMed  CAS  Google Scholar 

  • Bach FH, Robson SC, Winkler H, Ferran C, Stuhlmeier KM, Wrighton CJ and Hancock WW (1995). Barriers to xenotransplantation. Nat. Med. 1:869–873

    Article  PubMed  CAS  Google Scholar 

  • Battini JL, Danos O and Heard JM (1995). Receptor-binding domain of murine leukemia virus envelope glycoproteins. J. Virol. 69:713–719

    PubMed  CAS  Google Scholar 

  • Battini JL, Rasko JEJ and Miller D (1999) A human cell-surface receptor for xenotropic and polytropic murine leukimia viruses: possible role in G-proteincoupled signal transduction. Proc. Natl. Acad. Sci. 96:1385–1390

    Article  PubMed  CAS  Google Scholar 

  • Bennet W, Bjorkland A, Sundberg B, Brandhorst D, Brendel MD, Richards A, White DJ, Nilsson B, Groth CG and Korsgren O (2001) Expression of complement regulatory proteins on islets of Langerhans: a comparison between human islets and islets isolated from normal and hDAF transgenic pigs. Xenotransplantation 2: 100–105

    Google Scholar 

  • Bosch S, Arnould C and Jestin A (2000) Study of full-length porcine endogenous retrovirus genomes with envelope gene polymorphism in a specific-pathogen-free Large White swine herd. J Virol 74:8575–8581

    Article  PubMed  CAS  Google Scholar 

  • Cappello F, Stassi G, Lazzereschi D, Renzi L, Di Stefano C, Marfe G, Giancotti P, Wang HJ, Stoppacciaro A, Forni M, Bacci ML, Turchi V, Sinibaldi P, Rossi M, Bruzzone P, Pretagostini R, Della Casa G, Cortesini R, Frati L and Lavitrano M (2000) hDAF expression in hearts of transgenic pigs obtained by sperm-mediated gene transfer. Transplant Proc 32:892–894

    Article  PubMed  Google Scholar 

  • Carrington CA and dos Santos Cruz G (2000) Effect of cell surface concentration of human DAF on transgenic pig aortic endothelial cells on the degree of protection afforded against human complement deposition. Expert Opin Pharmacother 3:757–769

    Google Scholar 

  • Clemenceau B, Jegou D, Martignat L and Sai P (2001) Long-term follow-up failed to detect in vitro transmission of full-length porcine endogenous retroviruses from specific pathogen-free pig islets to human cells. Diabetologia 44:2044–2055

    Article  PubMed  CAS  Google Scholar 

  • Coffin JM (1984) Endogenous viruses. 2nd ed. In ¡°RNA tumor viruses¡± (R. Weiss, N. Teich, H. Varmus, and J. Coffin, Eds.), pp. 1109–1203. Cold Spring Harbor Laboratory Press, New York.

    Google Scholar 

  • Coffin JM (1996) Retroviridae: The viruses and their replication. In: Fields virology,3rd ed; Edit.: Fields BN, Knipe DM, Howley PM et al. 1767–1847

    Google Scholar 

  • Cornetta K, Moen RC, Culver K, Morgan RA, McLachlin JR, Sturm S, Selegue J, London W, Blaese RM and Anderson WF (1990) Amphotropic murine leukemia retrovirus is not an acute pathogen for primates. Hum Gene Ther 1:15–30

    Article  PubMed  CAS  Google Scholar 

  • Czauderna F, Fischer N, Boller K, Kurth R and Tönjes RR (2000) Establishment and characterization of molecular clones of porcine endogenous retroviruses replicating on human cells. J. Virol. 74:4028–4038

    Article  PubMed  CAS  Google Scholar 

  • Deng YM, Lee HJ, Moran C, Jin JH, Tuch BE and Rawlinson WD (2000) Mapping dispersed repetitive loci using semi-specific PCR cloning and somatic cell hybrid mapping. Nucleic Acid Res 28: E103

    Article  PubMed  CAS  Google Scholar 

  • Echard G (1974) Chromosomal banding patterns and karyotype evolution in three pig kidney cell strains (PK15, F and RP). Chromosoma 45:133–49

    Article  PubMed  CAS  Google Scholar 

  • Fischer N, Krach U, Niebert M and TÖnjes RR (2003) Detection of porcine endogenous retrovirus (PERV) using highly specific antisera against Gag and Env. Virology (in press)

    Google Scholar 

  • Fishman JA (1994). Miniature swine as organ donors for man: stratagies for prevention of xenotransplant-associated infections. Xenotransplantation 1:47–57

    Article  Google Scholar 

  • Fishman JA (1997) Xenosis and xenotransplantation: addressing the infectious risks posed by an emerging technology. Kidney Int. 51:41–45

    Google Scholar 

  • Fox M and McHale J (1998) Xenotransplantation: the ethical and legal ramifications. Med Law Rev 6:42–61

    Article  PubMed  Google Scholar 

  • Galbraith DN, Kelly HT, Dyke A, Reid G, Haworth C, Beekman J, Shepherd A and Smith KT (2000) Design and validation of immunological tests for the detection of Porcine endogenous retrovirus in biological materials. J Virol Methods 90:115–124

    Article  PubMed  CAS  Google Scholar 

  • Gimbel W, Schmidt J, Brack-Werner R, Luz A, Strauss PG, Erfle V and Werner T (1996) Molecular and pathogenic characterization of the RFB osteoma virus: lack of oncogene and induction of osteoma, osteopetrosis, and lymphoma. Virology 224:533–538

    Article  PubMed  CAS  Google Scholar 

  • Herring C, Cunningham DA, Whittam AJ, Fernandez-Suarez XM and Langford GA (2001a) Monitoring xenotransplant recipients for infection by PERV. Clin. Biochem.34:23–27

    CAS  Google Scholar 

  • Herring C, Quinn G, Bower R, Parsons N, Logan NA, Brawley A, Elsome K, Whittam A, Fernandez-Suarez XM, Cunningham D, Onions D, Langford G and Scobie L (2001b) Mapping full-length porcine endogenous retroviruses in a large white pig. J Virol 75:12252–12265

    Article  PubMed  CAS  Google Scholar 

  • Hiasa A, Watanabe M, Okada H, Ikenaka K, Fujita T, Yoshimatsu T, Kanematsu T and Shiku H (1999) Retroviruses prepared from human DAF expressing murine packaging cells acquire resistance against human serum. Int J Oncol 14:1091–1096

    PubMed  CAS  Google Scholar 

  • Hunkeler D, Sun AM, Korbutt S, Rajotte RV, Gill RG, Calafiore R and Morel P (1999). Bioartificial organs and acceptable risk. Nature Biotechn. 17:1045

    Article  CAS  Google Scholar 

  • Krach U, Fischer N, Czauderna F and Tönjes RR (2001). Comparison of replicationcompetent molecular clones of porcine endogenous retrovirus class A and class B derived from pig and human cells. J Virol 75:5465–5472

    Article  PubMed  CAS  Google Scholar 

  • Krach U, Fischer N, Czauderna F, Kurth R and T_njes RR (2000) Generation and testing of a highly specific anti-serum directed against porcine endogenous retrovirus nucleocapsid. Xenotransplantation 7:1–10

    Article  Google Scholar 

  • Lai L, Kolber-Simonds D, KW Park, HT Cheong, JL Greenstein, GS Im, Samuel M, A Bonk, Rieke A, Day BN, Murphy CN, Carter DB, Hawley RJ and Prather RS (2002) Production of $#x007B;alpha;$#x007B;-1,3-Galactosyltransferase Knockout Pigs by Nuclear Transfer Cloning. Science 295:1089–1092

    Article  PubMed  CAS  Google Scholar 

  • Leibovitch MP, Leibovitch SA, Hillion J, Guillier M and Harel J (1987) Expression of C-type virus in non differentiating rat myoblasts correlates with neoplastic progression. Biochem Biophys Res Commun 142:1111–1119

    Article  PubMed  CAS  Google Scholar 

  • LeTissier P, Stoye JP, Takeuchi Y, Patience C and Weiss RA (1997). Two sets of human-tropic pig retroviruses. Nature 389:681–682

    Article  CAS  Google Scholar 

  • Li M, Xu F, Muller J, Hearing VJ and Gorelik E (1998) Ecotropic C-type retrovirus of B16 melanoma and malignant transformation of normal melanocytes. Int J Cancer 76:430–436

    Article  PubMed  CAS  Google Scholar 

  • Limjoco TI, Dickie P, Ikeda H and Silver J (1993) Transgenic Fv4 mice resistant to Friend virus. J Virol 67:4163–4168

    PubMed  CAS  Google Scholar 

  • Martin U, Kiessig V, Blusch JH, Haverich A, von der Helm K, Herden T and Steinhoff G (1998) Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells. Lancet 352:692–694

    Article  PubMed  CAS  Google Scholar 

  • Martiney MJ, Rulli K, Beaty R, Levy LS and Lenz J (1999) Selection of reversion and suppressors of a mutation in the CBF binding site of a lymphomagenic retrovirus. J Virol 73:7599–7606

    PubMed  CAS  Google Scholar 

  • Matthews AL, Brown J, Switzer W, Folks TM, Heneine Wand Sandstrom PA (1999) Development and validation of a Western immunoblot assay for detection of antibodies to porcine endogenous retrovirus.Transplantation 67:939–943

    Article  PubMed  CAS  Google Scholar 

  • Mayer J, Sauter M, Röcz A, Scherer D, Mueller-Lantzsch N and Meese E (1999) An almost-intact human endogenous retrovirus K on humanchromosome 7 Nature Genetics 21:257–258

    Article  PubMed  CAS  Google Scholar 

  • Michaels MG and Simmons RL (1994) Xenotransplant-associated zoonoses. Transplantation 57:1–7

    Article  PubMed  CAS  Google Scholar 

  • Miyagawa S, Tanemura M, Koyota S, Koma M, Ikeda Y, Shirakura R and Taniguchi N (1999) Masking and reduction of the Galactose-alpha1,3-Galactose (alpha-Gal) epitope, the major xenoantigen in swine, by the glycosyltransferase gene transfection. Biochem Biophys Res Commun 264:611–614

    Article  PubMed  CAS  Google Scholar 

  • Niebert M, Rogel-Gaillard C, Chardon P and Tö njes RR (2002). Characterization of chromosomally assigned replication-competent gamma porcine endogenous retroviruses derived from a large white pig and expression in human cells. J Virol 76: 2714–2720

    Article  PubMed  CAS  Google Scholar 

  • Oldmixon BA, Wood JC, Ericsson TA, Wilson CA, White-Scharf ME, Andersson G, Greenstein JL, Schuurman HJ and Patience C (2002) PERV Transmission Characteristics of an Inbred Herd of Miniature Swine. J Virol 76:3045–3048

    Article  PubMed  CAS  Google Scholar 

  • Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, Chapman LE, Lockey C, Onions D, The XEN 111 Study Group and Otto E (1999). Search for cross-species transmission of porcine endogenous retrovirus in patients treated with liver pig tissue. Science 285:1236–1241.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Patience C, Takeuchi Y and Weiss RA (1997) Infection of human cells by an endogenous retrovirus of pigs. Nature Medicine 3:282–286

    Article  PubMed  CAS  Google Scholar 

  • Pitkin Z and Mullon C (1999) Evidence of absence of porcine endogenous retrovirus (PERV) infection in patients treated with a bioartificial liver support system. Artif Organs 23:829–833

    Article  PubMed  CAS  Google Scholar 

  • Powell SK, Gates ME, Langford G, Gu ML, Lockey C, Long Z and Otto E (2000) Antiretroviral agents inhibit infection of human cells by porcine endogenous retroviruses. Antimicrob. Agents Chemother. 44:3432–3433

    Article  CAS  Google Scholar 

  • Qari SH, Magre S, Garcia-Lerma JG, Hussain AI, Takeuchi Y, Patience C, Weiss RA and Heneine W (2001) Susceptibility of the porcine endogenous retrovirus to reverse transcriptase and protease inhibitors. J Virol 75:1048–1053

    Article  PubMed  CAS  Google Scholar 

  • Reiss MJ (2000) The ethics of xenotransplantation. J Appl Philos 17:253–262

    Article  PubMed  CAS  Google Scholar 

  • Rogel-Gaillard C, Bourgeaux N, Billault A, Vaiman M and Chardon P (1999) Construction of a swine BAC library: application to the characterization and mapping of the porcine type C endoviral elements. Cytogenet. Cell Genet. 85:205–211

    Article  CAS  Google Scholar 

  • Sandrin MS and McKenzie IF (1994) Gal alpha (1,3)Gal, the major xenoantigen(s) recognized in pigs by human natural antibodies. Immunol Rev 141:169–190

    Article  PubMed  CAS  Google Scholar 

  • Sandrini MS, Fodor WL, Mouhtouris E, Osman N, Cohney S, Rollins SA, Guilmette ER, Setter E, Squinto SP and McKenzie IF (1995) Enzymatic remodelling of the carbohydrate surface of a xenogeneic cell substantially reduce human antibody binding and complement mediated cytolysis. Nature Medicine 1:1261–1267.

    Article  Google Scholar 

  • Scheef G, Fischer N, Krach U and Tö njes 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 75:6933–6940

    Article  PubMed  CAS  Google Scholar 

  • Scheef G, Fischer N, Flory E, Schmitt I and Tönjes RR (2002) Transcriptional regulation of porcine endogenous retroviruses released from porcine and infected human cells by heterotrimeric protein complex NF-Y and impact of immunosuppressive drugs. J Virol 76:12553–12563

    Article  PubMed  CAS  Google Scholar 

  • Stephan O, Schwendemann J, Specke V, Tacke SJ, Boller K and Denner J (2001) Porcine endogenous retroviruses (PERVs): generation of specific antibodies, development of an immunoperoxidase assay (IPA) and inhibition by AZT. Xenotransplantation 8:310–316

    Article  PubMed  CAS  Google Scholar 

  • Stoye JP and Coffin JM (1995) The danger of xenotransplantation. Nature Medicine 1:1100

    Article  PubMed  CAS  Google Scholar 

  • Tacke SJ, Bodusch K, Berg A and Denner J (2001) Sensitive and specific immunological detection methods for porcine endogenous retroviruses applicable to experimental and clinical xenotransplantation. Xenotransplantation 8:125–135

    Article  PubMed  CAS  Google Scholar 

  • Takefman DM, Spear GT, Saifuddin M and Wilson CA (2002) Human CD59 incorporation into porcine endogenous retrovirus particles: Implications for the use of transgenic pigs for xenotransplantation. J Virol. 76:1999–2002.

    Article  PubMed  CAS  Google Scholar 

  • Takefman DM, Wong S, Maudru T, Peden K and Wilson CA (2001) Detection and characterization of porcine endogenous retrovirus in porcine plasma and porcine factor VIII. J Virol 75:4551–4557

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi Y, Patience C, Magre S, Weiss RA, Banerjee PT, LeTissier P and Stoye JP (1998) Host range and interference studies of three classes of pig endogenous retrovirus. J. Virol. 72:9986–9991

    PubMed  CAS  Google Scholar 

  • Tönjes RR, Czauderna F and Kurth R (1999) Genome wide screening, cloning, chromosomal assignment and expression of full-length human endogenous retrovirus type K (HERV-K). J Virol 73:9187–9195

    PubMed  Google Scholar 

  • Tönjes RR, Czauderna F, Fischer N, Krach U, Boller K, Chardon P, Rogel-Gaillard C, Niebert M, Scheef G Werner A and Kurth R (2000) Molecularly cloned porcine endogenous retroviruses replicate on human cells. Transplant Proc. 32:1158–1161

    Article  PubMed  Google Scholar 

  • Tönjes RR, Löwer R, Boller K, Denner J, Hasenmaier B, Kirsch H, K_nig H, Korbmacher C, Limbach C, Lugert R, Phelps RC, Scherer J, Thelen K, L_wer J and Kurth R (1996) HERV-K: the biologically most active human endogenous retrovirus family. J Acquir Immune Defic Syndr Hum Retrovirol 13:261–267

    Article  Google Scholar 

  • Turner G, Barbulescu M, Su M, Jensen-Seaman MI, Kidd KK and Lenz J (2001) Insertional polymorphisms of full-length endogenous retroviruses in humans. Curr Biol 11:1531–1535

    Article  PubMed  CAS  Google Scholar 

  • Van der Laan LJW, Lockey C, Griffeth BC, Fraisier FS, Wilson CA, Onions DE, Hering BJ, Long Z, Otto E, Torbett BE and Salomon DR (2000) Infection by porcine en-dogenous retrovirus after islet xenotransplantation in SCID mice. Nature 407:90–94

    Article  PubMed  Google Scholar 

  • Venables PJW, Brookes SM, Griffiths D, Weiss RA and Boyd MT (1995) Abundance of an endogenous retroviral envelope protein in placental trophoblasts suggests a biological function. Virology 211:589–592

    Article  PubMed  CAS  Google Scholar 

  • Weiss RA (1998) Transgenic pigs and virus adaptation. Nature 391:327–328

    Article  PubMed  CAS  Google Scholar 

  • Weiss RA (2000) Ancient and modern retroviruses. Acta Microbiol Immunol Hung 47:403–410

    PubMed  CAS  Google Scholar 

  • Wilson CA, Wong S, Muller J, Davidson CE, Rose TM and Burd P (1998) Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells. J Virol 72:3082–3087

    PubMed  CAS  Google Scholar 

  • Wilson CA, Wong S, Van Brocklin M and Federspiel M (2000) Extended analysis of the in vitro tropism of porcine endogenous retrovirus. J Virol 74:49–56

    Article  PubMed  CAS  Google Scholar 

  • Wolgamot G and Miller AD (1999) Replication of Mus dunni endogenous retrovirus depends on promoter activation followed by enhancer multimerization. J. Virol. 73:9803–9809

    PubMed  CAS  Google Scholar 

  • Woods T (1998) Have a heart: xenotransplantation, nonhuman death and human distress. Soc Anim 6:47–65.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, Langen, Germany

    M. Niebert & R.R Tönjes

Authors
  1. M. Niebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R.R Tönjes
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM 55, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Daniel R. Salomon M.D.

  2. Division of Cellular and Gene Therapies Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, FDA Building 29B, Room 2NN11 8800 Rockville Pike, HFM-530, Bethesda, MD, 20892, USA

    Carolyn Wilson M.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Niebert, M., Tönjes, R. (2003). Molecular Cloning and Functional Characterization of Infectious PERV and Development of Diagnostic Tests. In: Salomon, D.R., Wilson, C. (eds) Xeno-transplantation. Current Topics in Microbiology and Immunology, vol 278. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55541-1_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-55541-1_8

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-62431-5

  • Online ISBN: 978-3-642-55541-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation