Absence of PERV infection in baboons after transgenic porcine liver perfusion1

Nishitai, Ryuta; Ikai, Iwao; Shiotani, Tomohiro; Katsura, Nagato; Matsushita, T.; Yamanokuchi, Satoshi; Matsuo, Koichi; Sugimoto, Shinichi; Yamaoka, Yoshio

doi:10.1016/j.jss.2004.09.006

Cited by 27 publications

(18 citation statements)

References 36 publications

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“…These NHP species therefore lack the major infection route potentially used by PERV in humans. This fact must be taken into account in pig-to-NHP transplantation, where cynomolgus macaque and baboon are currently the most often used NHP species [48], and have been preferentially employed in PERV transmission studies in vivo [28], [29], [30], [31], [32]. The negative PERV transmission results in such experiments should be interpreted with caution.…”

Section: Discussionmentioning

confidence: 99%

“…Ongoing preclinical transplantation trials using non-human primates (NHP) as recipients of porcine cells, tissues and organs present the opportunity to assess the zoonosis risk in vivo [27], [28], [29], [30], [31], [32]. NHP offer the opportunity to evaluate the risk of PERV transmission after a long exposure to the pig xenograft, a variety of tissue can be analysed and the immunosuppression required can be simulated.…”

Section: Introductionmentioning

confidence: 99%

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Suboptimal Porcine Endogenous Retrovirus Infection in Non-Human Primate Cells: Implication for Preclinical Xenotransplantation

Mattiuzzo

Takeuchi

2010

PLoS ONE

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BackgroundPorcine 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.Principal FindingsTwo 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.ConclusionsSince 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Suboptimal Porcine Endogenous Retrovirus Infection in Non-Human Primate Cells: Implication for Preclinical Xenotransplantation

Mattiuzzo

Takeuchi

2010

PLoS ONE

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“…No evidence of PERV transmission was detected by molecular and serologic methods, in either the cultured cells of the human graft or in the blood of the recipient monkeys [13 ]. Absence of PERV infection was also documented after transgenic porcine liver perfusion in baboons and in 27 pig-tobaboon kidney and heart xenotransplantation procedures with a protocol involving depletion of galactose a(1,3) galactose (a-Gal) antibodies [14,15]. No PERV was detected in the blood of nonimmunosuppressed nonhuman primates transplanted with porcine islet cells as long as 8 weeks after transplantation [16,17].…”

Section: Transmissionmentioning

confidence: 95%

Infectious risk in xenotransplantation

Mueller

Fishman

2006

Current Opinion in Organ Transplantation

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“…Although PERVs can infect (non‐productively) cells of non‐human primates (NHPs) in vitro , transplantations of porcine tissues and inoculations with highly concentrated PERV preparations under immunosuppression into NHP in vivo demonstrated no PERV transmission or infection, respectively. However, later investigations demonstrated that the major receptor for PERV‐A is mutated in NHP, and therefore, the infection is not efficient .…”

Section: What Is New Since 2009: Perv Updatementioning

confidence: 99%

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Chapter 5: recipient monitoring and response plan for preventing disease transmission

Denner

Tönjes

Takeuchi

et al. 2016

Xenotransplantation

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Xenotransplantation of porcine cells, tissues, and organs may be associated with the transmission of porcine microorganisms to the human recipient. A previous, 2009, version of this consensus statement focused on strategies to prevent transmission of porcine endogenous retroviruses (PERVs). This version addresses potential transmission of all porcine microorganisms including monitoring of the recipient and provides suggested approaches to the monitoring and prevention of disease transmission. Prior analyses assumed that most microorganisms other than the endogenous retroviruses could be eliminated from donor animals under appropriate conditions which have been called "designated pathogen-free" (DPF) source animal production. PERVs integrated as proviruses in the genome of all pigs cannot be eliminated in that manner and represent a unique risk. Certain microorganisms are by nature difficult to eliminate even under DPF conditions; any such clinically relevant microorganisms should be included in pig screening programs. With the use of porcine islets in clinical trials, special consideration has to be given to the presence of microorganisms in the isolated islet tissue to be used and also to the potential use of encapsulation. It is proposed that microorganisms absent in the donor animals by sensitive microbiological examination do not need to be monitored in the transplant recipient; this will reduce costs and screening requirements. Valid detection assays for donor and manufacturing-derived microorganisms must be established. Special consideration is needed to preempt potential unknown pathogens which may pose a risk to the recipient. This statement summarizes the main achievements in the field since 2009 and focus on issues and solutions with microorganisms other than PERV.

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Absence of PERV infection in baboons after transgenic porcine liver perfusion1

Cited by 27 publications

References 36 publications

Suboptimal Porcine Endogenous Retrovirus Infection in Non-Human Primate Cells: Implication for Preclinical Xenotransplantation

Suboptimal Porcine Endogenous Retrovirus Infection in Non-Human Primate Cells: Implication for Preclinical Xenotransplantation

Infectious risk in xenotransplantation

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Chapter 5: recipient monitoring and response plan for preventing disease transmission

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