Suboptimal porcine endogenous retrovirus infection in non-human primate cells: implication for preclinical xenotransplantation

• Published in: PloS one 2010-10, Vol.5 (10), p.e13203-e13203
• Main Authors: Mattiuzzo, Giada, Takeuchi, Yasuhiro
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Analysis; Animal experimentation; Animals; Cells, Cultured; Cercopithecus aethiops; Cynomolgus; Deoxyribonucleic acid; DNA; Endogenous Retroviruses - pathogenicity; Genomes; Glycosylation; Health aspects; Health risks; In vivo methods and tests; Infection; Infections; Leucine; Macaca mulatta; Medical research; Molecular Sequence Data; Monkeys & apes; Papio; Porcine endogenous retrovirus; Primates; Proteinase-activated receptor 1; Receptors; Receptors, Virus - chemistry; Receptors, Virus - physiology; Retroviridae Infections - therapy; Retroviridae Infections - virology; Risk assessment; Sequence Homology, Amino Acid; Serine; Species; Sugar; Swine; Transplantation; Transplantation, Heterologous; Tunicamycin; Tunicamycin - pharmacology; Virions; Virology; Virology/Animal Models of Infection; Virology/Host Invasion and Cell Entry; Viruses; Xenografts; Xenotransplantation; Zoonoses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013203

Porcine endogenous retrovirus (PERV) poses a potential risk of zoonotic infection in xenotransplantation. Preclinical transplantation trials using non-human primates (NHP) as recipients of porcine xenografts present the opportunity to assess the zoonosis risk in vivo. However, PERV poorly infects NHP cells for unclear reasons and therefore NHP may represent a suboptimal animal model to assess the risk of PERV zoonoses. We investigated the mechanism responsible for the low efficiency of PERV-A infection in NHP cells. Two steps, cell entry and exit, were inefficient for the replication of high-titer, human-tropic A/C recombinant PERV. A restriction factor, tetherin, is likely to be responsible for the block to matured virion release, supported by the correlation between the levels of inhibition and tetherin expression. In rhesus macaque, cynomolgus macaque and baboon the main receptor for PERV entry, PERV-A receptor 1 (PAR-1), was found to be genetically deficient: PAR-1 genes in these species encode serine at amino acid 109 in place of the leucine in human PAR-1. This genetic defect inevitably impacts in vivo sensitivity to PERV infection of these species. In contrast, African green monkey (AGM) PAR-1 is functional, but PERV infection is still poor. Although the mechanism is unclear, tunicamycin treatment, which removes N-glycosylated sugar chains, increases PERV infection, suggesting a possible role for the glycosylation of the receptors. Since cynomolgus macaque and baboon, species often used in pig-to-NHP xenotransplantation experiments, have a defective PAR-1, they hardly represent an ideal animal model to assess the risk of PERV transmission in xenotransplantation. Alternatively, NHP species, like AGM, whose both PARs are functional may represent a better model than baboon and cynomolgus macaque for PERV zoonosis in vivo studies.