Absence of Replication of Porcine Endogenous Retrovirus and Porcine Lymphotropic Herpesvirus Type 1 with Prolonged Pig Cell Microchimerism after Pig-to-Baboon Xenotransplantation

Abstract

Porcine endogenous retrovirus (PERV), porcine cytomegalovirus (PCMV), and porcine lymphotropic herpesvirus (PLHV) are common porcine viruses that may be activated with immunosuppression for xenotransplantation. Studies of viral replication or transmission are possible due to prolonged survival of xenografts in baboon recipients from human decay-accelerating factor transgenic or ␣-1,3-galactosyltransferase gene knockout miniature swine. Ten baboons underwent xenotransplantation with transgenic pig organs. Graft survival was 32 to 179 days. Recipient serial samples of peripheral blood mononuclear cells (PBMC) and plasma were analyzed for PCMV, PERV, and PLHV-1 nucleic acids and viral replication using quantitative PCR assays. The PBMC contained PERV proviral DNA in 10 animals, PLHV-1 DNA in 6, and PCMV in 2. PERV RNA was not detected in any PBMC or serum samples. Plasma PLHV-1 DNA was detected in one animal. Pig cell microchimerism (pig major histocompatibility complex class I and pig mitochondrial cytochrome c oxidase subunit II sequences) was present in all recipients with detectable PERV or PLHV-1 (85.5%). Productive infection of PERV or PLHV-1 could not be demonstrated. The PLHV-1 viral load did not increase in serum over time, despite prolonged graft survival and pig cell microchimerism. There was no association of viral loads with the nature of exogenous immune suppression. In conclusion, PERV provirus and PLHV-1 DNA were detected in baboons following porcine xenotransplantation. Viral detection appeared to be due to persistent pig cell microchimerism. There was no evidence of productive infection in recipient baboons for up to 6 months of xenograft function.

Microbial safety in xenotransplantation

“…Consistent with this notion PLHV-1 DNA was detected in peripheral blood mononuclear cells (PBMCs) and plasma of recipient baboons after pig organ solid organ transplantation [10 ]. Productive infection was absent, and in all cases pig cell microchimerism was found.…”

“…Pig donors originating from a special designated pathogen-free herd were free of PCMV DNA [9]. In a separate trial of pig solid organ transplantation into baboon recipients PCMV DNA was detected in baboon blood samples after transplantation only in two recipients who had received organs from swine donors raised prior to the institution of an early weaning strategy to exclude PCMV [10 ].…”

Monitoring of porcine and baboon cytomegalovirus infection in xenotransplantation

“…Studies have demonstrated that early weaning of piglets is an effective method for maintaining the donor organs free of CMV, thus negating risks of PCMV reactivation in the recipient primate following organ transplantation [4,8]. However, the finding in the present study of one PCMV‐positive donor tissue raises the question of whether early‐weaning is entirely effective, and indicates that periodic assessment of the PCMV status of the donor pig herd is warranted.…”

Recent Progress in Xenotransplantation, with Emphasis on Virological Safety

“…The clinical symptoms of experimental porcine PTLD, such as fever, lethargy, anorexia, high white blood cell count, and palpable lymph nodes, are similar to those of human PTLD, which was linked to the human herpesvirus Epstein-Barr virus, now designated HHV-4 [77]. Evidence of productive PLHV-1 infection was not detected in recipient baboons receiving different organs from transgenic pigs for up to 6 months of transplant function [78]. Appropriate breeding procedures can eliminate PLHV and piglets free of PLHV were produced via Caesarean section and barrier-reared breeding procedure [74].…”