Recombinant porcine endogenous retroviruses (PERV‐A/C): a new risk for xenotransplantation?
Authors: Denner J. 
Published: April 2010

The zoonotic transmissions from non‐human primates of the human immunodeficiency virus (HIV‐1) that initiated the AIDS pandemic and the spread of many emerging infectious diseases teaches us that there is a need for carefully consider the potential risks associated with xenotransplantation. Whereas known viruses can easily be eliminated from donor pigs by designated pathogen free (DPF) breeding of the animals, this is not possible for porcine endogenous retroviruses (PERVs) that are integrated into the pig genome. Two such viruses, PERV‐A and PERV‐B, are present in all pigs and are able to infect human cells, whereas PERV‐C is not ubiquitous and only infects pig cells. In addition to these viruses, recombinant PERV‐A/C viruses were recently described [1‐3] that are able to infect human cells, are characterised by very high titre replication [4] and whose proviruses have been found de novo integrated in the DNA of somatic pig cells, but not yet in the pig germ line. However, since the receptor for PERV‐A/C is expressed on germ cells, infection of these cells is a theoretical possibility. Infection and integration of PERV‐A/C into the DNA of oocytes or sperm cells may lead to an endogenisation of the recombinant virus and transmission to offspring. PERV‐A/C viruses were also found in pigs with a very high incidence of melanomas although in this case the proviruses were found integrated in immune cells but not in tumour cells or in the germ line [5].

The risk posed by PERV‐A/C recombinant viruses for xenotransplantation could theoretically be eliminated by using pigs free of PERV‐C, as this would preclude recombination with PERV‐A [6]. However, when the incidence of PERV‐C in different pig strains and multitransgenic pigs was evaluated, 97.2% were found to have PERV‐C in their germ line [7]. To help overcome difficulties in obtaining animals free of PERV‐C, transgenic pigs were generated that express siRNA able to reduce expression of PERV‐A, PERV‐B and PERV‐C by RNA interference [8]. This should contribute to a low expression all PERV proviruses and therefore to a lower risk of recombination.

Supported by Deutsche Forschungsgemein‐schaft, DFG, DE729/4.

References

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

2. Wood JC, Quinn G, Suling KM, Oldmixon BA, Van Tine BA, Cina R, Arn S, Huanq CA, Scobie L, Onions DE, Sachs DH, Schuurmann HJ, Fishman JA, Patience C. Identification of exogenous forms of human‐tropic porcine endogenous retrovirus in miniature swine. J Virol 2004; 78: 2494–2501.

3. Bartosch B, Stefanidis D, Myers R, Weiss R, Patience C, Takeuchi Y. Evidence and consequence of porcine endogenous retrovirus recombination. J Virol 2004; 78: 13880–13890.

4. Denner J, Specke V, Thiesen U, et al. Genetic alterations of the long terminal repeat of an ecotropic porcine endogenous retrovirus (PERV) during passage in human cells. Virology 2003; 314: 125–133.

5. Dieckhoff B, Puhlmann J, Büscher K, Hafner‐Marx A, Herbach N, Bannert N, Büttner M, Wanke R, Kurth R, Denner J. Expression of porcine endogenous retroviruses PERVs in melanomas of Munich miniature swine MMS troll. Vet Microbiol 2007; 123: 53–68.

6. Denner J. Recombinant porcine endogenous retroviruses (PERV‐A/C): a new risk for xenotransplantation? Arch Virol 2008; 153: 1421–1426.

7. Dieckhoff B, Kessler B, Jobst D, Kues W, Petersen B, Pfeifer A, Kurth R, Niemann H, Wolf E, Denner J. Distribution and expression of porcine endogenous retroviruses (PERV) in multi‐transgenic pigs generated for xenotransplantation. Xenotransplantation 2009; 16: 64–73.

8. Dieckhoff B, Karlas A, Petersen B, Kues WA, Kurth R, Niemann, Denner J. Knockdown of porcine endogenous retrovirus (PERV) expression by PERV‐specific shRNA in transgenic pigs. Xenotransplantation 2008; 15: 36–45.