Review on porcine endogenous retrovirus detection assays--impact on quality and safety of xenotransplants

Antonia W Godehardt, Michael Rodrigues Costa, Ralf R Tönjes, Antonia W Godehardt, Michael Rodrigues Costa, Ralf R Tönjes

Abstract

Xenotransplantation of porcine organs, tissues, and cells inherits a risk for xenozoonotic infections. Viable tissues and cells intended for transplantation have to be considered as potentially contaminated non-sterile products. The demands on microbial testing, based on the regulatory requirements, are often challenging due to a restricted shelf life or the complexity of the product itself. In Europe, the regulatory framework for xenogeneic cell therapy is based on the advanced therapy medicinal products (ATMP) regulation (2007), the EMA CHMP Guideline on xenogeneic cell-based medicinal products (2009), as well as the WHO and Council of Europe recommendations. In the USA, FDA guidance for industry (2003) regulates the use of xenotransplants. To comply with the regulations, validated test methods need to be established that reveal the microbial status of a transplant within its given shelf life, complemented by strictly defined action alert limits and supported by breeding in specific pathogen-free (SPF) facilities. In this review, we focus on assays for the detection of the porcine endogenous retroviruses PERV-A/-B/-C, which exhibit highly polymorphic proviral loci in pig genomes. PERVs are transmitted vertically and cannot be completely eliminated by breeding or gene knock out technology. PERVs entail a public health concern that will persist even if no evidence of PERV infection of xenotransplant recipients in vivo has been revealed yet. Nevertheless, infectious risks must be minimized by full assessment of pigs as donors by combining different molecular screening assays for sensitive and specific detection as well as a functional analysis of the infectivity of PERV including an adequate monitoring of recipients.

Keywords: RNA-Seq; cocultivation; microarray analysis; porcine endogenous retrovirus; xenotransplantation.

© 2015 The Authors. Xenotransplantation Published by John Wiley & Sons Ltd.

References

    1. Manji RA, Ekser B, Menkis AH, Cooper DK. Bioprosthetic heart valves of the future. Xenotransplantation. 2014;21:1–10.
    1. Zhou H, Iwase H, Wolf RF, et al. Are there advantages in the use of specific pathogen-free baboons in pig organ xenotransplantation models? Xenotransplantation. 2014;21:287–290.
    1. Seifarth W, Spiess B, Zeilfelder U, et al. Assessment of retroviral activity using a universal retrovirus chip. J Virol Methods. 2003;112:79–91.
    1. Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10:57–63.
    1. Zou W, Chen D, Xiong M, et al. Insights into the increasing virulence of the swine-origin pandemic H1N1/2009 influenza virus. Sci Rep. 2013;3:1601.
    1. Wilson CA, Wong S, Muller J, et al. Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells. J Virol. 1998;72:3082–3087.
    1. Wynyard S, Nathu D, Garkavenko O, Denner J, Elliott R. Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand. Xenotransplantation. 2014;21:309–323.
    1. Denner J, Tönjes RR. Infection barriers to successful xenotransplantation focusing on porcine endogenous retroviruses. Clin Microbiol Rev. 2012;25:318–343.
    1. Kimsa MC, Strzalka-Mrozik B, Kimsa MW, et al. Porcine endogenous retroviruses in xenotransplantation-molecular aspects. Viruses. 2014;6:2062–2083.
    1. Waechter A, Denner J. Novel neutralising antibodies targeting the N-terminal helical region of the transmembrane envelope protein p15E of the porcine endogenous retrovirus (PERV) Immunol Res. 2014;58:9–19.
    1. Karlas A, Kurth R, Denner J. Inhibition of porcine endogenous retroviruses by RNA interference: increasing the safety of xenotransplantation. Virology. 2004;325:18–23.
    1. Dieckhoff B, Karlas A, Hofmann A, et al. Inhibition of porcine endogenous retroviruses (PERVs) in primary porcine cells by RNA interference using lentiviral vectors. Arch Virol. 2006;152:629–634.
    1. Dieckhoff B, Petersen B, Kues WA, et al. Knockdown of porcine endogenous retrovirus (PERV) expression by PERV-specific shRNA in transgenic pigs. Xenotransplantation. 2008;15:36–45.
    1. Ramsoondar J, Vaught T, Ball S, et al. Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs. Xenotransplantation. 2009;16:164–180.
    1. Ivics Z, Garrels W, Mátés L, et al. Germline transgenesis in pigs by cytoplasmic microinjection of Sleeping Beauty transposons. Nat Protoc. 2014;9:810–827.
    1. Hai T, Teng F, Guo R, Li W, Zhou Q. One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell Res. 2014;24:372–375.
    1. Wilson CA, Wong S, Vanbrocklin M, Federspiel MJ. Extended analysis of the in vitro tropism of porcine endogenous retrovirus. J Virol. 2000;74:49–56.
    1. Semaan M, Rotem A, Barkai U, Bornstein S, Denner J. Screening pigs for xenotransplantation: prevalence and expression of porcine endogenous retroviruses in Göttingen Minipigs. Xenotransplantation. 2013;20:148–156.
    1. Rodrigues Costa M, Fischer N, Gulich B, Tönjes RR. Comparison of porcine endogenous retroviruses infectious potential in supernatants of producer cells and in cocultures. Xenotransplantation. 2014;21:162–173.
    1. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med. 1997;3:282–286.
    1. Ericsson TA, Takeuchi Y, Templin C, et al. Identification of receptors for pig endogenous retrovirus. Proc Natl Acad Sci USA. 2003;100:6759–6764.
    1. Garkavenko O, Wynyard S, Nathu D, et al. Porcine endogenous retrovirus transmission characteristics from a designated pathogen-free herd. Transplant Proc. 2008;40:590–593.
    1. Irgang M, Karlas A, Laue C, et al. Porcine endogenous retroviruses PERV-A and PERV-B infect neither mouse cells in vitro nor SCID mice in vivo. Intervirology. 2005;48:167–173.
    1. Kaulitz D, Mihica D, Dorna J, et al. Development of sensitive methods for detection of porcine endogenous retrovirus-C (PERV-C) in the genome of pigs. J Virol Methods. 2011;175:60–65.
    1. Wynyard S, Garkavenko O, Elliot R. Multiplex high resolution melting assay for estimation of Porcine Endogenous Retrovirus (PERV) relative gene dosage in pigs and detection of PERV infection in xenograft recipients. J Virol Methods. 2011;175:95–100.
    1. Wang D, Coscoy L, Zylberberg M, et al. Microarray-based detection and genotyping of viral pathogens. Proc Natl Acad Sci USA. 2002;99:15687–15692.
    1. Wang D, Urisman A, Liu YT, et al. Viral discovery and sequence recovery using DNA microarrays. PLoS Biol. 2003;1:257–260.
    1. Lin B, Blaney KM, Malanoski AP, et al. Using a resequencing microarray as a multiple respiratory pathogen detection assay. J Clin Microbiol. 2007;45:443–452.
    1. Lin B, Malanoski AP, Wang Z, et al. Universal detection and identification of avian influenza virus by use of resequencing microarrays. J Clin Microbiol. 2009;47:988–993.
    1. Hsiue HC, Huang YT, Kuo YL, et al. Rapid identification of fungal pathogens in positive blood cultures using oligonucleotide array hybridization. Clin Microbiol Infect. 2010;16:493–500.
    1. Ballarini A, Segata N, Huttenhower C, Jousson O. Simultaneous quantification of multiple bacteria by the BactoChip microarray designed to target species-specific marker genes. PLoS One. 2013;8:e55764.
    1. Chen JX, Chen MX, Ai L, et al. A protein microarray for the rapid screening of patients suspected of infection with various food-borne helminthiases. PLoS Negl Trop Dis. 2012;6:e1899.
    1. Tenenbaum JD, Sansone SA, Haendel M. A sea of standards for omics data: sink or swim? J Am Med Inform Assoc. 2014;21:200–203.
    1. Miller MB, Tang YW. Basic concepts of microarrays and potential applications in clinical microbiology. Clin Microbiol Rev. 2009;22:611–633.
    1. Wheelan SJ, Martínez Murillo F, Boeke JD. The incredible shrinking world of DNA microarrays. Mol BioSyst. 2008;4:726–732.
    1. Stoughton RB. Applications of DNA microarrays in biology. Annu Rev Biochem. 2005;74:53–82.
    1. Hughes TR, Mao M, Jones AR, et al. Expression profiling using microarrays fabricated by an ink-jet oligonucleotide synthesizer. Nat Biotechnol. 2001;19:342–347.
    1. MAQC Consortium. Shi L, Reid LH, Jones WD, et al. The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements. Nat Biotechnol. 2006;24:1151–1161.
    1. Arezi B, Guha N, Bergstrom Lucas A Agilent Technologies. Gene Expression Profiling and Validation Using Agilent SurePrint G3 Gene Expression Arrays. Gene Expression Microarrays, 5990-9953EN, 05/11/2013.
    1. Leproust E Agilent Technologies. Agilent's Microarray Platform: How High-Fidelity DNA Synthesis Maximizes the Dynamic Range of Gene Expression Measurements. Gene Expression Microarrays, 5989-9159EN, 05/11/2013.
    1. Godehardt AW, Tönjes RR. Update on assays for detection of PERVs. Xenotransplantation. 2013;20:363.
    1. Groenen MA, Archibald AL, Uenishi H, et al. Analyses of pig genomes provide insight into porcine demography and evolution. Nature. 2012;491:393–398.
    1. Xu W, Seok J, Mindrinos MN, et al. Human transcriptome array for high-throughput clinical studies. Proc Natl Acad Sci USA. 2011;108:3707–3712.
    1. Robertson G, Schein J, Chiu R, et al. De novo assembly and analysis of RNA-Seq data. Nat Methods. 2010;7:909–912.
    1. Łabaj PP, Leparc GG, Linggi BE, et al. Characterization and improvement of RNA-Seq precision in quantitative transcript expression profiling. Bioinformatics. 2011;27:383–391.
    1. Gunawan A, Sahadevan S, Neuhoff C, et al. RNA deep sequencing reveals novel candidate genes and polymorphisms in boar testis and liver tissues with divergent androstenone levels. PLoS One. 2013a;8:e63259.
    1. Gunawan A, Sahadevan S, Cinar MU, et al. Identification of the novel candidate genes and variants in boar liver tissues with divergent skatole levels using RNA deep sequencing. PLoS One. 2013b;8:e72298.
    1. Hackl H, Burkard TR, Sturn A, et al. Molecular processes during fat cell development revealed by gene expression profiling and functional annotation. Genome Biol. 2005;6:R108.
    1. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products and Amending Directive 2001/83/EC Regulation (EC) No 726/2004.
    1. EMEA/CHMP/CPWP/83508/2009; Committee for Medicinal Products for Human Use (CHMP) Guideline on Xenogeneic Cell-Based Medicinal Products.
    1. EMEA/CHMP/410896/2006; Committee for Medicinal Products for Human Use (CHMP) Guideline on Human Cell-Based Medicinal Products.
    1. EMA/CAT/CPWP/686637/2011; Committee for Advanced Therapies (CAT) Draft Guideline on the Risk-based Approach According to Annex I, part IV of Directive 2001/83/EC Applied to Advanced-therapy Medicinal Products.
    1. The Changsha Communiqué. First WHO Global Consultation on Regulatory Requirements for Xenotransplantation Clinical Trials: Changsha, China, 19-21 November 2008. Xenotransplantation. 2009;16:61–63.
    1. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use.
    1. Regulation (EC) No 726/2004 of The European Parliament and of the Council of 31 March 2004 Laying Down Community Procedures for the Authorisation and Supervision of Medicinal Products for Human and Veterinary Use and Establishing a European Medicines Agency.
    1. Fishman JA, Scobie L, Takeuchi Y. Xenotransplantation-associated infectious risk: a WHO consultation. Xenotransplantation. 2012;19:72–81.
    1. Cozzi E, Tallacchini M, Flanagan EB, et al. The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes–chapter 1: Key ethical requirements and progress toward the definition of an international regulato ry framework. Xenotransplantation. 2009;16:203–214.
    1. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Biologics Evaluation and Research (CBER) 2002. Draft Guidance for Industry: Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood Products from Xenotransplantation Product Recipients and Their Intimate Contacts, February.
    1. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Biologics Evaluation and Research (CBER) 2003. Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans, April.
    1. Noel L. Global regulatory requirements for xenotransplantation clinical trials. Xenotransplantation. 2012;19:71.
    1. Tönjes RR. Safe transplantation. Lifeline. Medical research for healthy lives. Int Innov. 2013;1:82–83.

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