Abstract
Routine large‐scale xenotransplantation from pigs to humans is getting closer to clinical reality owing to several state‐of‐the‐art technologies, especially the ability to rapidly engineer genetically defined pigs. However, using pig organs in humans poses risks including unwanted cross‐species transfer of viruses and adaption of these pig viruses to the human organ recipient. Recent developments in the field of virology, including the advent of metagenomic techniques to characterize entire viromes, have led to the identification of a plethora of viruses in many niches. Single‐stranded DNA (ssDNA) viruses are the largest group prevalent in virome studies in mammals. Specifically, the ssDNA viral genomes are characterized by a high rate of nucleotide substitution, which confers a proclivity to adapt to new hosts and cross‐species barriers. Pig‐associated ssDNA viruses include torque teno sus viruses (TTSuV) in the Anelloviridae family, porcine parvoviruses (PPV), and porcine bocaviruses (PBoV) both in the family of Parvoviridae, and porcine circoviruses (PCV) in the Circoviridae family, some of which have been confirmed to be pathogenic to pigs. The risks of these viruses for the human recipient during xenotransplantation procedures are relatively unknown. Based on the scant knowledge available on the prevalence, predilection, and pathogenicity of pig‐associated ssDNA viruses, careful screening and monitoring are required. In the case of positive identification, risk assessments and strategies to eliminate these viruses in xenotransplantation pig stock may be needed.
Highlights
Eight species of the Parvoviridae family classified under four genera are described (Table 1); ungulate protoparvovirus 1 [classical porcine parvovirus (PPV) or PPV1], ungulate tetraparvovirus 2 (PPV3), ungulate tetraparvovirus 3 (PPV2, known as porcine hokovirus or porcine partetravirus or porcine PARV4), ungulate copiparvovirus 2 (PPV4, PPV5 and PPV6), ungulate bocaparvovirus 2 [porcine bocavirus (PBoV) 1, 2 and 6], ungulate bocaparvovirus 3 (PBoV 5), ungulate bocaparvovirus 4 (PBoV 7), and ungulate bocaparvovirus 5 (PBoV 3, PBoV4.1 and PBoV4.2).[64,65]
SsDNA viruses infecting humans and pigs are widely prevalent and have high mutation rates. This high prevalence may not hinder the use of pig xenografts, as a recent report highlights that islet cells of pigs do not carry common pig viruses including porcine circovirus type 2 (PCV2) and PPV1, even if other cells such as peripheral blood monocytes (PBMCs) carry them.[116]
Xenotransplantation of islet cells from pigs to cynomolgus monkeys in preclinical trials and from pigs to human patients in clinical trials has been achieved without transmission of any pig viruses including Single-stranded DNA (ssDNA) viruses such as PPV, porcine circovirus 1 (PCV1), and PCV2.117,118 it should be noted that the donor pigs used in these studies, Auckland Island pigs of mixed European genetic heritage, were from a specific pathogen-free breeding unit and confirmed PCV1 and PCV2 negative.[117,118]
Summary
The first successful xenograft implantation of a chemically treated pig heart valve into a human was carried out more than 50 years ago, and pigs are a major source of these bioprosthetics.[1,2] xenotransplantation of porcine Langerhans islet cells to diabetic humans was first attempted in 1994, and efforts to make this an effective therapy are ongoing.[3,4] Owing to these precedents, pigs are considered the preferred donor species for xenotransplantation to humans, with recent promising trials of successful porcine kidney and heart xenotransplantation to nonhuman primates.[5,6] pigs are inexpensive, easy to breed in a controlled environment with large litter sizes, and the organ size of pigs is comparable to that of humans.
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