No in vivo infection of triple immunosuppressed non-human primates after inoculation with high titers of porcine endogenous retroviruses
Creators: name: Specke, Volker
name: Plesker, Roland
name: Wood, James
name: Coulibaly, Cheick
name: Suling, Kristen
name: Patience, Clive
name: Kurth, Reinhard
name: Schuurman, Henk-Jan
name: Denner, Joachim
Publisher: name: Robert Koch-Institut
Year: 2009
Subjects: subject: Animals
subject: DNA
subject: Female
subject: Male
subject: Viral/blood
subject: Transplantation
subject: Heterologous
subject: Cyclosporine/therapeutic use
subject: Drug Therapy
subject: Combination
subject: Endogenous Retroviruses/genetics
subject: Endogenous Retroviruses/pathogenicity
subject: Immunosuppressive Agents/therapeutic use
subject: Macaca mulatta/immunology
subject: Macaca nemestrina/immunology
subject: Methylprednisolone/therapeutic use
subject: Papio/immunology
subject: Primate Diseases/immunology
subject: Primate Diseases/prevention &amp; control
subject: Primate Diseases/virology
subject: Retroviridae Infections/immunology
subject: Retroviridae Infections/prevention &amp; control
subject: Retroviridae Infections/veterinary
subject: Sirolimus/therapeutic use
subject: Swine/virology
subject: 610 Medizin

description: Background: Porcine endogenous retroviruses (PERVs) released from pig tissue can infect selected human cells in vitro and therefore represent a safety risk for xenotransplantation using pig cells, tissues, or organs. Although PERVs infect cells of numerous species in vitro, attempts to establish reliable animal models failed until now. Absence of PERV transmission has been shown in first experimental and clinical xenotransplantations; however, these trials suffered from the absence of long-term exposure (transplant survival) and profound immunosuppression. Methods: We conducted infectivity studies in rhesus monkeys, pig-tailed monkeys, and baboons under chronic immunosuppression with cyclosporine A, methylprednisolone, and the rapamycin derivative. These species were selected because they are close to the human species and PERVs can be transmitted in vitro to cells of these species. In addition, the animals received twice, a C1 esterase inhibitor to block complement activation before inoculation of PERV. In order to overcome the complications of microchimerism, animals were inoculated with high titers of cell-free PERV. In addition, to enable transmission via cell–cell contact, some animals also received virus-producing cells. For inoculation the primate cell-adapted strain PERV/5° was used which is characterized by a high infectious titer. Produced on human cells, this virus does not express alpha 1,3 Gal epitopes, does not contain porcine antigens on the viral surface and is therefore less immunogenic in non-human primates compared with pig cell-derived virus. Finally, we present evidence that PERV/5° productively infects cells from baboons and rhesus monkeys. Results: In a follow-up period of 11 months, no antibody production against PERV and no integration of proviral DNA in blood cells was observed. Furthermore, no PERV sequences were detected in the DNA of different organs taken after necropsy. Conclusion: These results indicate that in a primate model, in the presence of chronic immunosuppression, neither the inoculation of cell-free nor cell-associated PERV using a virus already adapted to primate cells results in an infection; this is despite the fact that peripheral blood mononuclear cells of the same animals are infectible in vitro.