Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals?

Abstract

Porcine endogenous retroviruses (PERVs) are present in the genome of all pigs, they infect certain human cells and therefore pose a special risk for xenotransplantation using pig cells, tissues and organs. Xenotransplantation is being developed in order to alleviate the reduced availability of human organs. Despite the fact that PERVs are able to infect certain human cells and cells from other species, transmission of PERVs has not been observed when animals (including non-human primates) were inoculated with PERV preparations or during preclinical xenotransplantations. The data indicate that PERVs were not transmitted because they were not released from the transplant or were inhibited by intracellular restriction factors and innate immunity in the recipient. In a single study in guinea pigs, a transient PERV infection and anti-PERV antibodies were described, indicating that in this case at least, the immune system may also have been involved.

Expression profile of human porcine endogenous retrovirus A receptors (HuPAR‐1, HuPAR‐2) and transcription factor activator protein‐2γ (TFAP‐2C) genes in infected human fibroblasts—Model in vitro

“…Differences in the env gene and Env protein determine the PERV subtypes and their tropism . Virus entry into the host cell is essential for its replication cycle and depends on the presence of the adequate surface receptors . In humans, two PERV‐A receptors have been identified: human PERV‐A receptor 1 (HuPAR‐1) and human PERV‐A receptor 2 (HuPAR‐2) .…”

“…It has been shown that transcription factor activator protein‐2γ (TFAP‐2C) is one of the transcription factors involved in the expression of HuPAR‐2 in human villous trophoblast cells . The risk of host cell infection depends on the quantity and functionality of the receptors . Increase of the receptors’ number through the transfection of the rat cells rendered them more permissive to PERV infection …”

“…7 Virus entry into the host cell is essential for its replication cycle and depends on the presence of the adequate surface receptors. 8 In humans, two PERV-A receptors have been identified: human PERV-A receptor 1 (HuPAR-1) and human PERV-A receptor 2 (HuPAR-2). 9 They are also known as G protein-coupled receptors 172A (GPR172A) and 172B (GPR172B) [10][11][12] or human riboflavin transporter 3 (hRFT3) and human riboflavin transporter 1 (hRFT1), 13,14 and recently as solute carrier family 52 members 2 and 1 (SLC52A2 and SLC52A1), respectively.…”

“…17 The risk of host cell infection depends on the quantity and functionality of the receptors. 8 Increase of the receptors' number through the transfection of the rat cells rendered them more permissive to PERV infection. 18 Although, to date, no PERV infections have been noted in humans in vivo, the possibility of PERV transmission to various human cells, including primary human endothelial cells, human primary peripheral blood mononuclear cells, [19][20][21] and fibroblasts, 22,23 has been confirmed in vitro.…”

Theme issue on infections and safety—An introduction

“…Inactivation of genomic PERV by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas may be a solution to ban the risk of transmission of PERV . However, in all previous pre‐clinical (well knowing that non‐human primates are far from suitable models) and clinical xenotransplantations, no PERV has been transmitted . In addition, the influence of CRISPR/Cas on the pig genome is still not well analyzed; for example, off‐target effects by CRISPR/Cas9 or suppression of p53 and enhanced oncogenicity have not been studied .…”