Fryer, J.F.L.; (2005) Studies on porcine cytomegalovirus relevant to xenotransplantation. Doctoral thesis , University of London.

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Abstract

Xenotransplantation of porcine organs into humans provides a potential solution to the current shortage of human donor organs, but raises considerable safety concerns including the potential transmission of porcine infectious agents, particularly viruses, to humans. Porcine cytomegalovirus (PCMV) is a betaherpesvirus, which causes generalised infection in newborn piglets. It is endemic in world pig populations including those of high health status, and is transmitted horizontally and in utero. PCMV represents a potential risk in xenotransplantation since its human counterpart, HCMV, is frequently transmitted from the organ donor and reactivates posttransplant, where it is associated with end-organ disease and graft rejection. Qualitative and quantitative PCR assays were developed in order to investigate the quantity and organ distribution of PCMV in pigs being bred for xenograft organs, and to investigate when virus is acquired. PCMV was found to be a common infection in conventionally-reared CD55 transgenic Large White pigs, with virus detected in potential xenograft organs of adult pigs, and widely disseminated in tissues of 3-5 week-old piglets. Prospective monitoring of piglets from birth showed that virus was acquired post-natally, whilst no evidence of in utero infection was found in caesarean-derived, barrier-reared piglets. Although these results showed that PCMV could be eliminated from pigs being bred for xenograft organs, knowledge of antiviral susceptibility is essential as it would provide therapeutic options should clinical trials proceed. The effect of antiherpetics on the growth of PCMV in a pig fallopian tube cell line was determined by real-time PCR and indirect immunofluorescence (IIF). In this cell culture model, ganciclovir and cidofovir were the most effective against PCMV replication, however, some cytotoxicity was associated with the highest concentration of cidofovir tested. Finally, a recombinant protein-based serological assay for PCMV was developed, utilising PCMV glycoprotein B expression in a baculovirus system.

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