Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

Abstract

SUMMARY Xenotransplantation may be a solution to overcome the shortage of organs for the treatment of patients with organ failure, but it may be associated with the transmission of porcine microorganisms and the development of xenozoonoses. Whereas most microorganisms may be eliminated by pathogen-free breeding of the donor animals, porcine endogenous retroviruses (PERVs) cannot be eliminated, since these are integrated into the genomes of all pigs. Human-tropic PERV-A and -B are present in all pigs and are able to infect human cells. Infection of ecotropic PERV-C is limited to pig cells. PERVs may adapt to host cells by varying the number of LTR-binding transcription factor binding sites. Like all retroviruses, they may induce tumors and/or immunodeficiencies. To date, all experimental, preclinical, and clinical xenotransplantations using pig cells, tissues, and organs have not shown transmission of PERV. Highly sensitive and specific methods have been developed to analyze the PERV status of donor pigs and to monitor recipients for PERV infection. Strategies have been developed to prevent PERV transmission, including selection of PERV-C-negative, low-producer pigs, generation of an effective vaccine, selection of effective antiretrovirals, and generation of animals transgenic for a PERV-specific short hairpin RNA inhibiting PERV expression by RNA interference.

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

“…So far, no evidence for PERV infection in human porcine islet recipients has been reported [53,54]. However, as in vitro infection of human tumor cell lines and even primary cells has been documented [55,56], current recommendations call for selection of donors with low levels of genomic PERV copies and low PERV expression [53,57]. In this context, attempts to reduce or suppress PERV expression by genetic modification of donors have been made.…”

Recent Progress in Xenotransplantation, with Emphasis on Virological Safety

“…Like endogenous retroviruses from other species, including humans, they are part of the genome and therefore cannot be eliminated, as in many other potentially zoonotic microorganisms in pigs, by SPF or DPF breeding [5]. PERV-A and PERV-B are in the genome of all pigs; PERV-C is common, but not present in all pigs.…”

“…PERVs were also not transmitted in preclinical pig to non-human primate transplantations, or in infection experiments with small animals or non-human primates with or without pharmaceutical immunosuppression (for a review, see [5]). However, most of the individuals were not exposed for a long time to the xenotransplants and, with some exceptions (associated with parallel kidney allotransplantations), no immunosuppression had been applied.…”

“…To prevent transmission of PERVs, which are present in the genome of all pigs and cannot be eliminated by SPF/DPF breeding [5], several strategies have been developed. First, pigs can be selected that have a low copy number and a low expression at the RNA or protein level of PERV-A and PERV-B proviruses.…”

“…There are 2 ways to prevent rejection: by a knockout of the cellular enzyme a1,3GT (GTKO pigs), which is adding a-gal epitopes to pig cell surface molecules [3], and by expression of human complement-regulatory proteins such as hCD46, hCD55, and hCD59 on pig cells (for review, see [4]). Animals expressing different combinations of the complement-regulatory proteins have been created (for overview, see Table 2 in [5]). In addition, immune T cell responses were reduced by simultaneous expression of CTLA4-IgG and mutant MHC class II transactivator [6][7][8][9].…”