Introduction
With the development of regenerative medicine, transplantation has become the most effective solution for end-stage organ failure. While the main difficulty in transplantation is the critical shortage of available donor organs. Xenotransplantation, which uses animals as the organ source for human transplantation, could potentially overcome the shortage of human organs. Pigs, which are anatomically and physiologically comparable to humans, are the most suitable donor animal for xenotransplantation.
However, three significant barriers need to be overcome before xenotransplantation becomes a clinical therapy. They are immune rejection, physiological incompatibility, and cross-species transmission of porcine endogenous retroviruses (PERVs) between the human recipient and the porcine xenograft (Niu et al., 2021).
To date, with the development of genome engineering and animal cloning technologies, it becomes possible to obtain multigene genetically modified donor pigs to overcome the immunological and physiological obstacles. And a recent study showed a baboon lived with a cardiac xenograft from a three-gene (GTKO/hCD46/hTBM) modified pig survived beyond 900 days (Mohiuddin et al., 2016).
When analyzing the microbiological safety in xenotransplantation, PERVs pose the greatest threat. As an endogenous retrovirus, PERVs are integrated into the porcine genome and vertically transferred through inheritance (Denner, 2016), so PERVs cannot be eliminated by traditional ways such as designated or specified pathogen-free (DPF or SPF) breeding. In vitro experiments showed that PERVs could infect different human cells (Takeuchi et al., 1998), and recombinant PERVs released by infected human cells acquired resistance to complement-mediated killing (Patience, Takeuchi, & Weiss, 1997). Like other retroviruses, PERVs can insert their cDNA into the host cell genome, potentially leading to immunodeficiency or tumorigenesis (Denner & Tönjes, 2012). Meanwhile, Like most retrovirus, the transmembrane envelope protein of PERVs has a highly conserved immunosuppressive domain which can inhibit human immune cell function (Tacke, Kurth, & Denner, 2000). This indicates that a high titer of PERV particles in the recipient who receives a solid vascularized porcine organ transplant might lead to an immunodeficiency disease. Meanwhile, there is no evidence from previous studies that PERVs can infect human recipients in vivo. However, most of these patients were not exposed to porcine grafts for a long time, and no immunosuppressants were used as well (Dinsmore, Manhart, Raineri, Jacoby, & Moore, 2000; Matsumoto, Abalovich, Wechsler, Wynyard, & Elliott, 2016).
Over the last decades, much progress has been made. However, a series of questions, such as what are the physiological functions of PERVs, and whether PERVs infect humans in vivo , still need to be answered in order to implement pig-to-human xenotransplantation.
This review presented the current knowledges on PERVs as well as the potential impact of PERVs on immune system and xenotransplantation.