PERVs or porcine endogenous retroviruses are present in the nuclei of all pig cells so avoiding their transfer during xenotransplantation is practically impossible (1). If humans did get infected with PERVs from a xenotransplant, they’d need to get treated, same as with other retroviral infections.
- Rx with standard anti-retroviral drugs would be an obvious choice but which ones are effective against PERVs?
- Among used in humans, azidothymidine ( ) showed anti-PERV activity ( , 3). However, since azidothymidine is also quite toxic, it may not be realistically feasible, i.e., safe enough, for someone who’s also simultaneously undergoing immunosuppression, as patients with transplants do, or if used, it may be necessary to use at lower doses, in which case it may not be completely effective.
- Among newer anti-retrovirals, such as (4) and (3) have shown potent anti-PERV activity in vitro.
- Decades of experience in HIV also show that multi-drug therapy, i.e., using anti-retroviral drugs that target different viral pathways, is the optimal approach since it increases efficacy and reduces risk of drug resistance.
- The cutting-edge approach, specifically the system can inactivate multiple PERV loci ( ). This important proof-of-concept suggests it may be possible to proactively remove PERVs from pig graft tissue prior to transplanting into humans.
It’s also important to assess the likelihood of actual PERV transmission and there’s data to do so since >200 individuals have received some form of pig transplants (mainly pancreatic islets) or exposure (mainly to pig kidney, liver, neuronal or skin cells) in a variety of experimental studies. So far, there’s not a single report of PERV transmission to humans among these recipients (6, 7, see list below from).
However, in vitro data from more than one lab shows that PERVs can be transmitted in human cells exposed to pig-derived blood, plasma or cells in culture (9, 10,, ). Thus, though risk to humans is reportedly low (1, 10), nevertheless it’s tangible enough that it needs to be addressed with defined and rational scientific approaches ( , see quote below).
‘In general, it is likely that the development of surveillance techniques might be guided by the ‘‘Precautionary Principle.’’ That is, ‘the risk of xenogeneic infection is generally thought to be low but the deployment of appropriate procedures and assays should not wait until a risk is confirmed’ (World Health Organization. OECD/WHO Consultation on Xenotransplantation Surveillance—WHO. CDS/CSR/EPH/2001.2 (Guidance Document), 2000)’
1. Takeuchi, Yasuhiro, and Jay Fishman. “Long life with or without PERV.” Xenotransplantation 17.6 (2010): 429-430.
2. Qari, Shoukat H., et al. “Susceptibility of the porcine endogenous retrovirus to reverse transcriptase and protease inhibitors.” Journal of virology 75.2 (2001): 1048-1053.
3. Argaw, Takele, Winston Colon‐Moran, and Carolyn Wilson. “Susceptibility of porcine endogenous retrovirus to anti‐retroviral inhibitors.” Xenotransplantation 23.2 (2016): 151-158.
4. Demange, Antonin, et al. “Porcine endogenous retrovirus-A/C: biochemical properties of its integrase and susceptibility to raltegravir.” Journal of General Virology 96.10 (2015): 3124-3130.
5. Yang, Luhan, et al. “Genome-wide inactivation of porcine endogenous retroviruses (PERVs).” Science 350.6264 (2015): 1101-1104.
6. Heneine, Walid, et al. “No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts.” The Lancet 352.9129 (1998): 695-699.
7. Dinsmore, Jonathan H., et al. “NO EVIDENCE FOR INFECTION OF HUMAN CELLS WITH PORCINE ENDOGENOUS RETROVIRUS (PERV) AFTER EXPOSURE TO PORCINE FETAL NEURONAL CELLS1.” Transplantation 70.9 (2000): 1382-1389.
8. Denner, Joachim. “Xenotransplantation-Progress and Problems: A Review.” Journal of Transplantation Technologies & Research 2014 (2014).
9. Patience, Clive, Yasuhiro Takeuchi, and Robin A. Weiss. “Infection of human cells by an endogenous retrovirus of pigs.” Nature medicine 3.3 (1997): 282-286.
10. Le Tissier, Paul, et al. “Two sets of human-tropic pig retrovirus.” Nature 389.6652 (1997): 681-682.
11. Wilson, Carolyn A., et al. “Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells.” Journal of virology 72.4 (1998): 3082-3087.
12. Wood, James C., et al. “Identification of exogenous forms of human-tropic porcine endogenous retrovirus in miniature swine.” Journal of virology 78.5 (2004): 2494-2501.
13. Fishman, Jay A., Linda Scobie, and Yasuhiro Takeuchi. “Xenotransplantation‐associated infectious risk: a WHO consultation.” Xenotransplantation 19.2 (2012): 72-81.