Denner, Joachim

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Received: 1 December 2022 Revised: 8 February 2023 Accepted: 23March 2023DOI: 10.1111/xen.12800COMMEN TAR YFirst transplantation of a pig heart from amultiplegene-modified donor, porcine cytomegalovirus/roseolovirus,and antiviral drugsJoachim DennerInstitute of Virology, Free University Berlin, Berlin, GermanyCorrespondenceJoachimDenner, Institute of Virology, Free University Berlin, Robert vonOstertag-Straße 7, 14163 Berlin, Germany.Email: Joachim.Denner@fu-berlin.deFunding informationThe German Research Foundation, Grant/Award Number: TRR127KEYWORDSantibodies, antiviral drugs, porcince cytomegalovirus /porcine roseolovirus, virus safetyThe porcine cytomegalovirus (PCMV) is actually a porcine roseolovirus(PRV).1 As the official International Committee on Taxonomy ofViruses (ITCV) name, suid betaherpesvirus 2 (SuBHV2),2 is not widelyused, the abbreviation (PCMV/PRV) will be used to make clear thatit is a herpesvirus not closely related to the human cytomegalovirus(HCMV), but to the human herpesviruses 6 and 7 (HHV-6, HHV-7), which are also roseoloviruses.3 PCMV/PRV was shown to reducesignificantly the survival time of pig xenotransplants in non-humanprimates. Yamada et al.4 and Sekijima et al.5 reported a reductionof the survival time of pig kidneys from PCMV/PRV-positive donorpigs when transplanted in cynomolgus monkeys and baboons, respec-tively, in 2014. Already in 2002 Mueller et al.6 reported an activationPCMV in a pig-to-primate model of xenotransplantation in animalswith short survival times. In 2016 for the first time an active replica-tion of PCMV following transplantation of a pig heart into a baboondespite undetected virus in the donor pig was reported.7 Denneret al.8 reported a reduction of the survival time of genetically mod-ified pig hearts in baboons. For detailed reviews of these and otherstudies see Denner.9,10 PCMV/PRVwas also transmitted to the humanrecipient who received a pig heart in January 2022 in Baltimore,Maryland, USA.11 The clinical features and the steadily increasingvirus load observed in the patient in Baltimore are very similar tothe features and high virus load observed in baboons, which receiveda PCMV/PRV-positive heart in Munich.8 Therefore, it is likely thatthe virus contributed together with other factors to the death of theThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non-commercial and nomodifications or adaptations aremade.© 2023 The Authors. Xenotransplantation published by JohnWiley & Sons Ltd.patient.12–16 These additional factors were surgical problems, prob-lemswith immunosuppression, applicationof the IVIG, and theantiviraldrugs (see below).After transplantation the patient was treated six times with antivi-ral drugs developed mainly against HCMV (Figure 1). There wereearly publications indicating that antiviral drugs against HCMV areless efficient against PCMV/PRV.17,18 Since some of these drugs,for example, cidofovir are also used successfully against otherDNA viruses, for example, monkeypox or mpox virus,19 it is impor-tant to analyze, how effective the applied antivirals were againstPCMV/PRV.The PCMV/PRV infection was observed in the patient at day 20.11Ganciclovir and valacyclovir were given starting with day 0, and 19,respectively (Figure 1), possibly as a prophylactic measure to preventHCMVactivation, however, in thepublicationbyGriffith et al.11 HCMVwas not indicated as present in the patient.Ganciclovir is a nucleoside analogue, it is a derivative of aciclovirand exhibits in vitro activity against HCMV and herpes simplex virustypes 1 and 2 (HSV-1, HSV-2), and to a lesser degree against Epstein-Barr virus (EBV), varicella zoster virus (VZV), human herpesvirus - 6(HHV-6), andwith a very low efficiency against human adenoviruses.20Common adverse drug reactions include: granulocytopenia, neutrope-nia, anemia, thrombocytopenia, and others. Thrombocytopenia was amarked feature in the Baltimore patient.11 Ganciclovir is considerablymore potent than aciclovir againstHCMV.Valaciclovir, the L-valyl esterXenotransplantation. 2023;30:e12800. wileyonlinelibrary.com/journal/xen 1 of 3https://doi.org/10.1111/xen.12800DENNER 2 of 3F IGURE 1 Virus load of PCMV/PRV (red line) in the plasma of theBaltimore patient and treatment of the patient by antiviral drugsaccording to Griffith et al.11 The days of changing the antiviral drugs ortheir dose (black arrows) and the day of application of the IVIGpreparation (day 43, green arrow) are indicated.of aciclovir, is a prodrug, which is active after being converted to aci-clovir in the human body.21 Aciclovir is used for the treatment of HSVinfections, chickenpox, and shingles. Like aciclovir, ganciclovir cannoteradicate a latent herpesvirus infection.20When ganciclovir was applied to baboons given PCMV/PRV-positive pig hearts, it did not decrease the virus load of PCMV/PRV, i.e.,it had no therapeutic efficacy in vivo in achievable concentrations.17In vitro, PCMV/PRV was relatively resistant against ganciclovir andaciclovir. Only cidofovir and another drug, foscarnet, were found tohave a therapeutic efficacy in vivo in achievable concentrations. How-ever, cidofovir and foscarnetwere often significantly toxic in transplantrecipients.17 Similar results were also obtained in another study.18 Inthis cell culture system, ganciclovir and cidofovirwere effective againstPCMV/PRV, however, some toxicity was associated with the highestconcentration of cidofovir. Aciclovir and foscarnet were not effectivein this system.18After detection of PCMV/PRV at day 20, a permanent increase inthe virus load was observed in the Baltimore patient, showing thatganciclovir and valacyclovir were not effective against PCMV/PRV inthe patient. Consequentially, the antiviral therapy was changed fromganciclovir to cidofovir on day 43. Cidofovir is an acyclic phospho-nate nucleotide analogue of deoxycytidine monophosphate with abroader spectrum of activity against double-stranded DNA viruses,including human herpesviruses.22 It was approved for the treat-ment of HCMV induced retinitis in AIDS patients, which was thereason that some newspapers reported that the Baltimore patientswas treated with a drug against AIDS. The major dose-limiting sideeffect of cidofovir is nephrotoxicity,23 its half-life is between 2.6 and9.5 h.24But how effective was cidofovir in the Baltimore patient? After thefirst application at day 43 the virus titer was still increasing (Figure 1).The delay may be explained by the fact that cidofovir is acting onthe viral polymerase and therefore on the de novo production ofthe virus, but not on already produced virus. Starting with day 47the virus titer was decreasing, and a second application of cidofovirwas given on day 49. The titer was further decreasing until day 55,then it was increasing rapidly to a very high virus load. Was cidofovircausing the decline? It seems possible that in addition to cidofoviranother factor was involved in the reduction of the virus load: Onday 43, together with cidofovir, intravenous immune globulin (IVIG)was administered. IVIG are usually isolated from pooled plasma thathas been donated by 1000–100 000 people and they are used asreplacement therapy in primary and acquired humoral immunodefi-ciency and as an immunomodulatory therapy in autoimmune diseaseand transplantation.25 We recently have shown that antibodies againstHHV-6 are cross-reacting with PCMV/PRV.26 There are two HHV-6species, HHV-6A and HHV-6B, which cannot be discriminated sero-logically. HHV-6 has a high seroprevalence in the human populationof 95%–100% in humans older than 2 years of age.27,28 The Balti-more patient was also HHV-6 positive.11 Therefore, it is likely that theIVIG preparations contain antibodies against HHV-6 considering thehigh number of donors. Consequentially, it cannot be excluded that thereduction in the virus load of PCMV/PRV in the Baltimore patient afterday 47 was due to neutralizing antibodies and antibodies contributingto opsonization and clearing of the virus.29To summarize, the antiviral drugs (especially ganciclovir and valacy-clovir) applied to the Baltimore patient had only a very limited effecton PCMV/PRV. It is likely that PCMV/PRV and certain antibodies in theIVIGpreparation found tobedirected against pig tissues13 contributedto the death of the patient together with other factors. At present, itremains unclearwhether the antiviral drugs and their toxic effectsmayhave contributed.ACKNOWLEDGMENTSWork on xenotransplantation of the laboratory of the author was sup-ported by the German Research Foundation, TRR127. I would like tothank Prof. N. Mueller, Zurich, and Prof. B. Kaufer, Berlin, for criticalcomments.Open access funding enabled and organized by Projekt DEAL.CONFLICT OF INTEREST STATEMENTThe author has no conflict of interest.ORCIDJoachim Denner https://orcid.org/0000-0003-3244-6085REFERENCES1. Gu W, Zeng N, Zhou L, Ge X, Guo X, Yang H. Genomic organizationand molecular characterization of porcine cytomegalovirus. Virology.2014;460-461:165-172.2. https://ictv.global/report/chapter/herpesviridae/herpesviridae/roseolovirus3. Denner J, Bigley TM, Phan TL, Zimmermann C, Zhou X, Kaufer BB.Comparative analysis of roseoloviruses in humans, pigs, mice, andother species. Viruses. 2019;11(12):1108.4. Yamada K, Tasaki M, Sekijima M, et al. Porcine cytomegalovirus infec-tion is associated with early rejection of kidney grafts in a pig tobaboon xenotransplantation model. Transplantation. 2014;98(4):411-418.5. Sekijima M, Waki S, Sahara H, et al. Results of life-supporting galac-tosyltransferase knockout kidneys in cynomolgus monkeys using twodifferent sources of galactosyltransferase knockout Swine. Transplan-tation. 2014;98(4):419-426. 13993089, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/xen.12800 by Freie Universitaet Berlin, Wiley Online Library on [03/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License3 of 3 DENNER6. Mueller NJ, Barth RN, Yamamoto S, et al. Activation ofcytomegalovirus in pig-to-primate organ xenotransplantation. J.Virol. 2002;76(10):4734-4740.7. Morozov VA, Abicht JM, Reichart B, Mayr T, Guethoff S, DennerJ. Active replication of Porcine Cytomegalovirus (PCMV) followingtransplantation of a pig heart into a baboon despite undetected virusin the donor pig. Ann Virol Res. 2016;2(3):1018.8. Denner J, Längin M, Reichart B, et al. Impact of porcinecytomegalovirus on long-term orthotopic cardiac xenotransplantsurvival. Sci Rep. 2020;10(1):17531.9. Denner J. Xenotransplantation and porcine cytomegalovirus. Xeno-transplantation. 2015;22(5):329-335.10. Denner J. Reduction of the survival time of pig xenotransplants byporcine cytomegalovirus.Virol J. 2018;15(1):17111. Griffith BP, Goerlich CE, Singh AK, et al. Genetically modified porcine-to-human cardiac xenotransplantation. N Engl J Med. 2022;387(1):35-44.12. Denner J. The porcine cytomegalovirus (PCMV) will not stop xeno-transplantation. Xenotransplantation. 2022;29(3):e12763.13. Cooper DKC, Yamamoto T, Hara H, Pierson RN 3rd. The first clinicalpig heart transplant: was IVIg or pig cytomegalovirus detrimental tothe outcome? Xenotransplantation. 2022;29(4):e12771.14. Mueller NJ, Denner J. Porcine cytomegalovirus/porcine roseolovirus(PCMV/PRV): a threat for xenotransplantation? Xenotransplantation.2022;29(5):e12775.15. Fishman JA. Risks of infectious disease in xenotransplantation.NEngl JMed. 2022;387(24):2258-2267.16. Denner J, Schuurman HJ. Early testing of porcine organ xeno-transplantation products in humans: microbial safety as illustratedfor porcine cytomegalovirus. Xenotransplantation. 2022;29(6):e12783.Epub 2022Nov 6.17. Mueller NJ, Sulling K, Gollackner B, et al. Reduced efficacy of ganci-clovir against porcine and baboon cytomegalovirus in pig-to-baboonxenotransplantation. Am J Transplant. 2003;3(9):1057-1064.18. Fryer JF, Griffiths PD, Emery VC, Clark DA. Susceptibility ofporcine cytomegalovirus to antiviral drugs. J Antimicrob Chemother.2004;53(6):975-980.19. Harapan H, Ophinni Y, Megawati D, et al. Monkeypox: a comprehen-sive review. Viruses. 2022;14(10):2155.20. Faulds D, Heel RC. Ganciclovir. A review of its antiviral activity, phar-macokinetic properties and therapeutic efficacy in cytomegalovirusinfections.Drugs. 1990;39(4):597-638.21. Kausar S, Said Khan F, Ishaq Mujeeb Ur Rehman M, et al. A review:mechanism of action of antiviral drugs. Int J Immunopathol Pharmacol.2021;35:20587384211002621.22. Ahmed A. Antiviral treatment of cytomegalovirus infection. InfectDisord Drug Targets. 2011;11(5):475-503.23. JacobsenT, SifontisN.Drug interactions and toxicities associatedwiththe antiviral management of cytomegalovirus infection. Am J HealthSyst Pharm. 2010;67(17):1417-1425.24. Caruso Brown AE, Cohen MN, Tong S, et al. Pharmacokinetics andsafety of intravenous cidofovir for life-threatening viral infectionsin pediatric hematopoietic stem cell transplant recipients. AntimicrobAgents Chemother. 2015;59(7):3718-372525. Looney RJ, Huggins J. Use of intravenous immunoglobulin G (IVIG).Best Pract Res Clin Haematol. 2006;19(1):3-25.26. FiebigU,HolzerA, IvanusicD, et al. Antibody cross-reactivity betweenPorcineCytomegalovirus (PCMV)andHumanHerpesvirus-6 (HHV-6).Viruses. 2017;9(11):317.27. Braun DK, Dominguez G, Pellett PE. Human herpesvirus 6. Clin.Microbiol. Rev. 1997;10, 521-567.28. Gustafsson R, Svensson M, Fogdell-Hahn A. Modulatory effects ondendritic cells by human herpesvirus 6. Front Microbiol. 2015;6:388.29. Hetherington SV, Giebink GS. Opsonic activity of immunoglobu-lin prepared for intravenous use. J Lab Clin Med. 1984;104(6):977-986.How to cite this article: Denner J. First transplantation of apig heart from amultiple gene-modified donor, porcinecytomegalovirus/roseolovirus, and antiviral drugs.Xenotransplantation. 2023;30:e12800.https://doi.org/10.1111/xen.12800 13993089, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/xen.12800 by Freie Universitaet Berlin, Wiley Online Library on [03/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

First transplantation of a pig heart from a multiple gene-modified donor, porcine cytomegalovirus/roseolovirus, and antiviral drugs

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First transplantation of a pig heart from a multiple gene-modified donor, porcine cytomegalovirus/roseolovirus, and antiviral drugs

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