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      Porcine endogenous retroviruses: Quantification of the copy number in cell lines, pig breeds, and organs

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          Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9

          Xenotransplantation is a promising strategy to alleviate the shortage of organs for human transplantation. In addition to the concern on pig-to-human immunological compatibility, the risk of cross-species transmission of porcine endogenous retroviruses (PERVs) has impeded the clinical application of this approach. Earlier, we demonstrated the feasibility of inactivating PERV activity in an immortalized pig cell line. Here, we confirmed that PERVs infect human cells, and observed the horizontal transfer of PERVs among human cells. Using CRISPR-Cas9, we inactivated all the PERVs in a porcine primary cell line and generated PERV-inactivated pigs via somatic cell nuclear transfer. Our study highlighted the value of PERV inactivation to prevent cross-species viral transmission and demonstrated the successful production of PERV-inactivated animals to address the safety concern in clinical xenotransplantation.
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            Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand.

            Xenotransplantation using pig cells, tissues, or organs may be associated with the transmission of porcine microorganisms and the development of zoonoses. Among all porcine microorganisms porcine endogenous retroviruses (PERVs) represent a special risk because they are integrated in the genome of all pigs and able to infect human cells. In previous preclinical and retrospective clinical trials of xenotransplantation, no transmission of PERV was observed. The first clinical trial of (alginate-encapsulated) porcine islet cell transplantation in New Zealand, which was approved by the New Zealand Government as an open-label phase I/IIa safety/efficacy trial, offers the possibility to analyze microbiological safety in a prospective clinical study. Before the trial started, a multilevel testing strategy was used to screen for 26 microorganisms in donor pigs of the Auckland Island strain and the islet cell preparations used for treatment. Donor testing was performed using molecular methods including multiplex real-time PCR. Blood samples from 14 pig islet cell recipients were also investigated by molecular biological methods at weeks 1, 4, 8, 12, 24, and 52 post-transplant for the transmission of porcine microorganisms. Sera were also monitored at these time points for antibodies against PERVs. Beginning in 2009, fourteen patients with severe unaware hypoglycemia were treated with one of four different dosages of alginate-encapsulated porcine islets ranging from 5000-20,000 islet equivalents delivered in a single dose. No transmission of either PERVs or other porcine microorganisms was detected by PCR and immunological methods. These findings support previous results and strongly indicate the safety of xenotransplantation as performed here. © 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
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              Infection barriers to successful xenotransplantation focusing on porcine endogenous retroviruses.

              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.
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                Author and article information

                Journal
                Xenotransplantation
                Xenotransplantation
                Wiley
                0908665X
                July 2018
                July 2018
                August 18 2018
                : 25
                : 4
                : e12445
                Affiliations
                [1 ]Robert Koch Institute; Berlin Germany
                [2 ]School of Life Sciences Weihenstephan; Technische Universität München; Freising Germany
                [3 ]Molecular Animal Breeding and Biotechnology; Gene Center; Ludwig-Maximilians-Universität München; Oberschleißheim Germany
                Article
                10.1111/xen.12445
                30264881
                587db8a7-9da9-4c4f-a4ce-44a48c33c2a6
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

                http://onlinelibrary.wiley.com/termsAndConditions#vor

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