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.