potential risks of viral infections in xenotransplantation

Acta Tropica 76 (2000) 147–158

Potential risks of viral infections in xenotransplantation

Daudi K. Langat, Jason M. Mwenda *Institute of Primate Research, National Museums of Kenya, PO Box 24481, Karen, Nairobi, Kenya

Received 19 October 1998; received in revised form 16 February 2000; accepted 17 March 2000

Abstract

The shortage of cadaveric human organs for transplantation may, be alleviated by the use of xenografts as atherapeutic option for end-stage organ failure. Successful attempts have been made to prevent rejection of xenografttissues in humans. The potential spread of animal-derived pathogens to the xenograft recipient is a complication ofxenotransplantation, which must be addressed. This can be complicated further by, the presence of new pathogens,new clinical syndromes, and altered behaviour of these organisms in the immunocompromised recipient. There isconcern over the possible activation of latent viruses, including retroviruses, from xenograft tissues. This paperdiscusses the possible dangers of transmission of animal viruses to humans via xenotransplantation. © 2000 ElsevierScience B.V. All rights reserved.

Keywords: Transplantation; Herpesviruses; Xenografts; SIV/STLV-I; Endogenous retroviruses

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1. Introduction

Organ transplantation is one of the successstories of the twentieth century In the past 20years or so, results of transplantation havesteadily improved and currently, 80% of the pa-tients undergoing kidney, liver or heart transplan-tation survive up to 1 year, and 70% can surviveup to 5 years (Cooper, 1996). The major limitingfactor to organ transplantation today is the in-creasing shortage of suitable donor organs. Forexample, in the US, approximately 45 000 peopleare listed for solid organ transplantation, yet less

than 6000 cadaveric donors become available eachyear, from which approximately 20 000 donororgans are obtained (Cooper, 1996) The dis-crepancy between the number of potential recipi-ents and donor organs is increasing by,approximately 10–15% annually (Cooper, 1993).This problem may be alleviated by the use ofanimal organs (xenotransplantation), and someencouraging progress has been made in this area.

Xenotransplantation would ensure an unlimitednumber of organs and tissues. However, xeno-transplantation generally results in hyperacuterejection, i.e. destruction of the vascular endo-thelium of the donor organ within minutes ofexposure to human or monkey blood. The lysisoccurs through a complement-dependent mecha-nism following binding of naturally occurring

* Corresponding author. Tel.: +254-2-8825714; fax: +254-2-882546.

E-mail address: [email protected] (J.M. Mwenda).

0001-706X/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.

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D.K. Langat, J.M. Mwenda / Acta Tropica 76 (2000) 147–158148

antibodies to carbohydrate antigens on the glycol-ipids and glycoproteins of the donor cells. Themain xeno-antigen recognised is an a-(1-3)-galac-tose terminal sugar residue (aGal). Most mam-mals express a-(1-3)-galactosyitransferase, whichplaces aGal on glycoconjugates. Humans and oldworld primates lack this enzyme, and due toexposure to aGal antigen from various sourcessuch as bacteria in the gut, antibodies to aGalantigen are generally present in circulation (Weiss,1998), and this triggers the complement-mediatedlysis of xenogeneic cells bearing aGal antigens(Rother et al., 1995). Various strategies have beenused in an attempt to overcome these barriers toxenotransplantation. These include use of phar-macological immunosuppressive agents, depletion(in the recipient) of anti-pig antibodies or inhibi-tion of their attachment to graft antigens, anddepletion or inhibition of complement in the re-cipient (Cooper, 1996). Other methods which havebeen attempted include the development of im-munological tolerance in the recipient to donortissues by the creation of chimeras and the use ofgenetically engineered donor animals (especiallythe pig) whose organs do not lead to antibody-mediated complement activation following trans-plantation into a human. The progress that hasbeen made in xenotransplantation has recentlybeen reviewed (Chapman et al., 1995; Cooper,1996) So far, a number of xenotransplants havebeen performed, with varying rates of success.However, public concern has been raised regard-ing possible infections that may be associated withxenotransplantation. Viral infections have beentransmitted via transplantation of organs, tissueallografts such as bone, skin, cornea and heartvalves, and cells such as islets, haematopoleticstem cells, and semen (Eastlund, 1995). Primateretroviruses represent one group of pathogenswhich pose a major risk for the transmissionbetween concordant and discordant species. Theseinclude exogenous and retroviruses of non-humanprimates and other animals. The incidence of celland tissue transplant-transmitted infection is un-known, but it can be inferred either from prospec-tive, retrospective or case control studies. Despitestringent screening measures of potential organdonors, a risk of pathogen transmission still ex-

ists. This is more so in viral infections, especiallyendogenous retroviruses, whose role in normaltissues has not been elucidated.

2. Endogenous retroviruses

Endogenous retroviral sequences (ERVs) havebeen found in the genomes of most vertebratespecies. ERVs are defective due to presence ofmultiple termination codons, deletions or the lackof a 5% LTR, but some ERVs have complete openreading frames throughout some of the genes andcan be transcribed and expressed at protein levelin most human and non-human primate repro-ductive tissues (reviewed by Johnson et al., 1990;Mwenda, 1994; Urnovitz and Murphy, 1996; Tar-uscio and Mantovani, 1998) Their role in diseaseand normal cellular development in normal pri-mates is not known. In general, endogenous retro-viruses are not highly expressed, althoughoccasional transcription can occur. Due to adap-tations of the host-viral receptor proteins, manyotherwise intact endogenous retroviruses cannotinfect cells derived from their current host (Stoye,1997). However, viral replication can take place incells derived from different species. It has beenshown that an endogenous retrovirus of baboons(BaEV), one of cats (RD114) and some of micecan infect and replicate in human cell lines (Ben-veniste et al., 1974; Coffin, 1984). A pathologicalpotential of non-defective endogenous retro-viruses has so far only been demonstrated in mice,where they have been shown to be associated withinduction of tumours and immunological disor-ders (Coffin, 1984). In humans, ERVs have beenimplicated in certain pathological conditions in-cluding systemic lupus erythematosus (SLE),rheumatoid arthritis, Sjogren’s syndrome andmixed connective tissues diseases (reviewed inWilkinson et al., 1994), but their role in diseasedevelopment is not known.

Most endogenous xenotropic retroviruses areessentially non-pathogenic, hence transmissionwould have no consequence for either the recipi-ent or the society. However, it has been shownthat retroviruses resulting from recombination be-tween two murine retroviruses can cause

D.K. Langat, J.M. Mwenda / Acta Tropica 76 (2000) 147–158 149

lymphomas in macaques. It might be worth tak-ing the risk of xenotransplantation as long as thevirus is confined to the transplant recipient, but itis much more dangerous if the initial virus couldspread to the general population, possibly follow-ing mutational or recombinational events (Stoye,1997). There is also the danger that an endoge-nous retrovirus may be quiescent in its host spe-cies may become lethal when it is transferred to anew species as would occur during xenotransplan-tation. One of the species of animals that has beenconsidered as ideal as a source of xenografts forhumans is the pig. The pig is viewed as an idealdonor of cells, tissues and vascularised organs dueto a variety of practical, financial, safety andethical reasons. Human transplantation of ster-ilised pig heart valves is now routine, and acelularswine skin is also sometimes used as a temporarycover for burns. Foetal pig pancreas islets cellshave been transplanted into diabetic patients(Groth et al., 1994) and pig liver has been used asa transient perfusion support in a case of fulmi-nant hepatic failure (Makowka et al., 1995).Porcine insulin is used by millions of diabeticsworld-wide.

However, the pigs also contain an endogenousretrovirus, porcine endogenous retrovirus (PERV)which is a type C retrovirsus of about 8 kb withthe greatest nucleic acid sequence identity to Gip-pon ape leukaemia virus (GaLV) and murineleukaemia virus (MuLV) (Akiyoshi et al., 1998).Constitutive production of PERV mRNA hasbeen detected in normal leukocytes, and in multi-ple organs of the swine. Kidney, heart and spleentissues obtained from domestic pigs have beenfound to contain multiple copies of integratedPERV genomes and expressed viral RNA (Pa-tience et al., 1997). The expression of PERVmRNA varies with the type of tissue, with thehighest expression observed in the thymus, lungand peripheral blood leukocytes, and lowest inkidney, heart and liver (Akiyoshi et al., 1998). Pigkidney, cell lines (PK-15) spontaneously also pro-duce C-type retroviral particles. Cell-free retro-virus produced by the PK-15 cells has been shownto infect pig, mink and human kidney cell linesand co-cultivation of X-irradiated PK-15 cell lineswith human cells resulted in a broader range of

human cell infection, including human diploidfibroblasts and B- and T-cell lines (Patience et al.,1997). Infection of human cells or expression ofthe PERV virus in vivo has not been demon-strated. It appears that frequent contact betweenpigs and humans has never led to retrovirallyinduced disease, possibly because human comple-ment can lyse retroviruses that are grown in ani-mal cells (Takeuchi et al., 1996a) although othertypes of immune responses may be involved suchas the presence of xenoreactive natural antibodiesin potential transplant recipients (Bach, 1998).Under the circumstances of a transplant, i.e. closeproximity and long term contact, this barrier tospread could probably be overcome, especially asthe measures taken to reduce hyperacute rejectionand permit xenografting will reduce the efficiencyof lysis. Patience et al. (1997) showed that porcineretrovirus grown in human cells is no longersusceptible to lysis by human complement, imply-ing that once a viral breakout occurs, there will beno further barrier to spread by this resistancemechanism. Thus its; potential infectivity and ef-fects in humans cannot be disregarded. Whileattempts to genetically engineer pigs which cannotbe rejected by, the human immune cells are beingmade, attention should also be focused on beingable to breed pigs whose tissues do not producePERVs. The technology of ‘knocking out’ the piggenes that code for the viruses is not yet available,and because these viruses are endocenous, raisingvirus-free pigs will not be easy. It has been ob-served that many animal viruses with lipid en-velopes are sensitive to inactivation by humancomplement. Apparently this lysis is triggered bythe binding of anti-aGal antibodies in human serato aGal residues expressed on the viral envelope(Rother et al., 1995; Takeuchi et al., 1996b). Thusvirus inactivation occurs by precisely, the samemechanism as hyperacute rejection of xenografts.Hence modifications to make porcine xenograftsresistant to lysis may also make enveloped virusesof pigs similarly resistant to lysis, especially, inpigs transgenic for human complemention,proteins such as CD46, CD55 and CD59 (Weiss,1998). This most likely may occur when a lot ofhuman proteins are incorporated into the viralenvelope as suggested by studies showing that


human complementary proteins are present inHIV and can protect it from complement-medi-ated lysis (Montefiori et al., 1994). Also, PERVreleased from pig cells is highly sensitive to hu-man complement-mediated lysis, whereas thesame virus passaged in human cells lacking aGalimmediately becomes resistant (Patience et al.,1997), suggesting that acquisition of human com-plementary proteins may also confer resistance toPERV-infected cells.

Transgenic pigs may also provide an opportu-nity for animal viruses to adapt to a human hostrange. Human coxsackie B virus, for example, canbe adapted to grow in mice, and in some humancell cultures, increase its infectivity a million-foldby adopting the CD55 receptor (Bergelson et al.,1995). If pigs were to harbour picornaviruses thatuse the porcine equivalent of CD55, such virusesmight easily adapt to recognise CD55 in transge-nie pigs that express both native porcine and thehuman forms of the receptor. These viruses wouldthen be pre-adapted for transmission to the xeno-graft recipient and for human-to-human transmis-sion (Weiss, 1998). Also, not all the virusesinfection pigs have been discovered; only recently,a new porcine virus related to the human hepatitisvirus E was reported (Meng et al., 1997). Untilthe possible consequences of infection by, PERVare better understood it is unlikely that a signifi-cant number of porcine xenotransplants will pro-ceed. Although PERV grows only in low titres inhuman cells, hence are unlikely to be pathogenic,we cannot dismiss the possibility of virus adapta-tion or recombination with other retroviruses inthe new host.

A small number of patients have already beentreated with or exposed to living porcine cells ortissue, and investigation of these patients mayprovide valuable information. A recent study in-volving two renal dialysis patients whose circula-tion had been linked extracorporeally to pigkidneys did not show any evidence of seroconver-sion for PERV-specific antibodies (Patience et al.,1998a). There was also no evidence of either pigor PERV DNA in either patient. The absence ofporcine cells in the circulation of both patients,even in the samples taken soon after the perfusionexperiment, suggests that any porcine cells, dis-

lodged from the kidney became rapidly se-questered from the circulation. Since cell-to-cellcontact increases the efficiency of infection ofPERV, this removal of porcine cells may increasethe risk of transmission of PERV to the xenograftrecipient (Patience et al., 1998a). However, therewas no indication of infection of these patients byPERV, when tested using polymerase chain reac-tion (PCR) or neutralisation assay. Likewise, astudy to investigate the potential in vivo transferof PERV after xenotransplantation of primaryporcine aortic endothelial cells (PAEC) to im-munosuppressed baboons did not show anyPERV infection (Martin et al., 1998a), Endothe-lial cells are the main interface between a xeno-graft and the recipient’s leukocytes and tissues.PERV expression in PAEC was also analysed,and PERV mRNA and reverse transcriptase inthe culture supernatant could be detected. Despiteof the release of retroviral particles from culturedPAEC, transplantation of these cells into baboonrecipients did not result in virus transmission, noteven under heavy immunosuppression (Martin etal., 1998a). However, in vitro, it was observedthat PAECs, hepatocytes, lung, and skin from avariety of pig strains and breeds expressed PERVmRNA (Martin et al., 1998b), PAEC releasedinfectious particles, and cocultivation of PAECand HEK293 led to productive infection of thehuman cells and expression of PERV types A andB. The release of infectious virus from PAECoccurred without mitogenic stimulation, suggest-ing a serious risk of retrovirus transfer afterxenotransplantation.

It has been observed that expression of someretroviruses is reduced or lost when a tissue isgrafted, even though expression of the virus oc-curs in vitro. Fenjves et al. (1996) showed thatkeratinocytes transduced with a retrovirus encod-ing the gene for factor IX continued to secrete thisfactor in culture but when these cells were graftedto athymic mice, factor IX expression was re-duced or lost within 6 weeks. This would be goodnews for xenotransplantation for it would meanthat the dangers of endogenous retroviral infec-tion of the xenograft recipient from the donororgan would be eliminated. However, it becomesan obstacle to the use of retroviruses for gene


therapy, especially epidermal gene therapy. Alsothe growth and development of retroviral-infectedcells has been shown to be suppressed in vivo(Puddu et al., 1991). In an experiment involvingthe use of uninfected and chronically HIV-in-fected U937 cells, the uninfected cells were foundto develop large solid tumours when injected sub-cutaneously into nude mice, whereas the HIV-in-fected cells were not tumourigenic. However,these cells developed tumours when these cellswere passively immunised with antibody to alpha-beta interferon, and in mice which were eitherimmnosuppressed or genetically immunodeficient.A note of caution is also suggested for the use ofpseudotyped lentiviral vectors for human genetherapy, especially given the fact that there isdanger of interaction of retrovirus vectors andendogenous retrovirus present in packaging celllines and target cells may result in unwantedevents, such as the formation of recombinantviruses and the mobilisation of therapeutic vec-tors. A recent study by Patience et al. (1998b) toexamine human and murine gene therapy packag-ing cell lines for incorporation of endogenousretrovirus transcripts into murine leukaemia virus(MLV) vector particles and, conversely, whethervector genomes are incorporated into human en-dogenous retrovirus (HERV) particles producedsome interesting results. They showed that VL30endocierious retrovirus sequences were efficientlypackaged in particles produced by the murineAM12 packaging system However, although thehuman FLY packaging cells expressed severalclasses of HERV transcripts (HERV-K, HuRT,type C and RTVL-H), none was detectable in theMLV vector particles released from the cells.Non-specific packaging of the MLV gag-pol ex-pression vector transcripts was detected in theFLY virions at a low level (1 in 17 000 se-quences). These findings indicate that humanpackaging cells produce retrovirus particles farless contaminated by endogenous viral sequencesthan murine packaging cells. Human teratocar-cinoma cells (GH cells), which produce HERV-Kparticles, were transduced with an MLV-derivedbeta-Gal vector. Although both HERV-K andRTVL-H sequences were found in associationwith the particles, beta-Gal transcripts were not

detected, indicating that HERV Gag proteins donot efficiently package MLV-based vectors (Pa-tience et al., 1998b).

3. Exogenous retroviruses

Non-human primates harbour many retro-viruses including simian immunodeficiency viruses(SIV) (Hayami et al., 1994). SIVs are non-humanprimate lentiviruses that are closely related tohuman immunodeficiency virus (HIV), especiallyHIV-2. This similarity has led some scientists tosuggest that HIV might have arisen from simianretroviruses introduced to human hosts, wherethey adapted and spread (Karpas, 1990). SIVinfection has been found in African non-humanprimates especially among the anthropoid apesand the primates belonging to the genera Cercop-ithecus, Cercocebus and Papio (Ohta et al., 1988;Fultz et al., 1990). Cross-transmission of SIVfrom one non-human primate species to anotherhas been shown to occur in the wild especiallybetween species which share habitats. Forinstance, cross-transmission of SIVagm betweenbaboons and African green monkeys has beendemonstrated in the wild (Jin et al., 1994) al-though tile number was quite small (n=2), sug-gesting that cross-transmission may not bewell-established in the wild. Experimental infec-tion of the rhesus monkey (Macaca mulatta) withthe SIV isolate SIVmac leads to an AIDS-likedisease (Hirsch and Johnson, 1992), and SIVmne(SIV from the pigtalled macaque, Macacanemestrina) reproducibly causes a fatal AIDS-likedisease in other macaque species (Benveniste etal., 1988). SIV is genetically similar to HIV-2 andthis has led to the speculation that HIV may haveoriginated from non-human primates (Desrosiers,1990; Owusu, 1991). Evidence to support thishypothesis has been provided by studies of thephylogenetic relationships of various HIV-2,SIVsm and SIVmac lineages which suggest thatthe entire HIV-2/SIVsm/SIVmac group of viruseshave a common ancestor which infected sootymangabeys, and that HIV-2 in humans and SIV-mac in macaques are each the result cross-speciestransmission (Gao et al., 1994). It appears that


SIVmac was generated inadvertently by transferof SIVsm from naturally infected sootymangabeys to macaques in the settings of primatecentres. Similarly, naturally infected sootymangabeys also represent the probable source ofHIV-2 in the human population. The naturalhabitat of sooty mangabeys coincides with thegeographic pattern of HIV-2 endemicity in westAfrica (Marx et al., 1991; Gao et al., 1992), and inmany west African countries, sooty mangabeysare hunted for food and kept as pets (Marx et al.,1991). Thus scratches and bites of humans bymonkeys and exposure to monkey blood in thecontext of food preparation is common (Gao etal., 1994). SIV has also been shown to infecthumans. For instance, the presence of anti-SIVantibodies have been reported in two animal labo-ratory workers who accidentally sustained bloodexposures from infected animals (CDC, 1992).Neither has yet developed disease; consequently,it’s clinical relevance is uncertain. It has also beenisolated from humans living in west Africa (Bren-nan et al., 1997).

There is also a possibility that SIV could bctransmitted via a xenotransplant to the recipient,even though the laboratory tests indicate a flega-tive result. It has been shown that HIV-1 can betransmitted via allograft tissues (Simonds et al.,1992), In this case, the virus was transmitted bytransplantation of organs and tissues procuredbetween the time the donor became infected andthe appearance of antibodies. Four recipients ofsolid organs and three recipients of unprocessedfresh–frozen bone got infected with HIV-1. How-ever, 34 recipients of other tissues: two receivingcorneas, three receiving lyophilised soft tissue, 25receiving ethanol-treated bone, three receivingdura mater treated with gamma radiation, andone receiving marrow-evacuated, fresh–frozenbone., tested negative for HIV-1 antibody (Si-monds et al., 1992). This shows that althoughrare, transmission of viruses by seronegative or-gan and tissue donors can occur. This risk can beavoided in xenotransplantation by using animalswhich are raised in quarantined environments,where laboratory tests can be performed seriallyand using sensitive tests such as PCR to screensource animals.

Investigations into the use of baboons as organdonors for human transplant recipients haveraised the spectre of transmitting baboon virusesto humans and possibly establishing new humaninfectious diseases. Retrospective analysis of tis-sues from two human transplant recipients withend-stage hepatic disease who died 27 and 70 daysafter the transplantation of baboon livers revealedthe presence of two simian retroviruses of baboonorigin, simian foamy virus (SFV) and baboonendogenous virus (BaEV), in multiple tissue com-partments (Allan et al., 1998). The presence ofbaboon mitochondrial DNA was also detected inthese same tissues, suggesting that xenogeneic‘passenger leukocytes’ harbouring latent or, activeviral infections had migrated from the xenograftsto distant sites within the human recipients Thepersistence of SFV and BaEV in human recipientsthroughout the post-transplant period under-scores the potential infectious risks associatedwith xenotransplantation. Recently, Baboon bonemarrow was grafted into HIV-1-infected patientsin the course of recent trials for AIDS treatment(Lehrman, 1995) but no endogenous retroviruseswere detected in this case. Because of the presenceof multiple copies of an endogenous oncovirus inthe baboon genome, chimeric lenti-oncovirusescould emerge in the xenotransplant recipient. In astudy to analyse the potential replication compe-tence of hybrid viruses between different genera ofretroviruses, the en6 gene of simian immunodefi-ciency virus was replaced with the en6 gene of anamphotropic murine leukaemia virus (Reiprich etal., 1997). These researchers showed that the hy-brid virus could be propagated in human T-celllines, in peripheral blood mononuclear cells ofrhesus macaques, and in CD4+ B-cell lines. Be-cause of the expanded cell tropism, the hybridvirus might have a selective advantage in compari-son to parental viruses. Therefore, emergingchimeric viruses may be considered a serious riskof xenotransplantation.

Another retrovirus which is of great importancein xenotransplantation is simian T-lymphotrophicvirus type I (STLV-I). STLV-I has been found tobe closely related to human T-lymphotrophicvirus type I (HTLV-I) which is the causative agentof adult T-cell leukaemia (ATL) and has also


been linked to neurological disorders in humans.STLV-1 has a 90% sequence homology with theen6, Px and LTR regions of HTLV-I. A preva-lence rate of 20–40% of STLV-I has been foundin wild and captive baboon populations (Kankiand Essex, 1988). Seroepidemiologic studies haveshown STLV-I is prevalent only among OldWorld monkeys and apes, but not among NewWorld monkeys (Ishikawa et al., 1987); but inspider monkeys (Ateles fusciceps), a retroviruswhich resembles HTLV-II has been detected, anddesignated STLV-II (Chen et al., 1994). Furtherstudies have shown STLV-I infection results in anATL-like disease in monkeys (Noda et al., 1986;Tsujimoto et al., 1987). A seroepidenilologic studyby Homma et al. (1984) in macaques found anincreased incidence of STLV-I antibodies in ani-mals with lymphoma or lyniphoproliferative dis-eases, implicating this virus as the causative agentof these diseases. Given that non-human primatesharbour STLV-I infections, it is possible thatprimate organs may transmit this pathogen tohumans. Due to the ease and availability ofreagents to test for presence of infection of theseretroviruses in potential donor animals, the trans-mission via xenotransplants call be avoided. How-ever, most of the test kits available commerciallyare designed to detect human pathogens, andthese kits are sometimes used to test for retroviralinfection in non-human primates due to the closesimilarity of the human and non-human primateretroviruses. It is not clear whether the sensitivityof these kits in detecting retroviruses in non-hu-man primates is similar to that ill human retro-viruses. They may not be able to detect very lowlevels of viral infections. Thus, a xenograft withvery low levels of a retrovirus may transfer thevirus to humans, and the effect of this oil theimmunocompromised recipient is not known.

The human foamy virus (HFV) and simianfoamy virus (SFV) may also be of considerableimportance in xenotransplantation. HFV, a pro-totype of the spumavirus, has been shown to havetranscription features different from that of onco-and lentiviruses (Weiss, 1996). Foamy viruses arecommonly found in primates (especially the greatapes) but rarely in humans (Weiss, 1988; Flugel,1991). Recent studies have shown that humans

can become infected with SFV and these fewindividuals exhibit specific immune responses toSFV (Desrosiers, 1990; Heneine et al., 1998). Inone of the studies, 1.8% (4/231) of humans occu-pationally exposed to non-human primates werefound to be infected with SFV (Heneine et al.,1998). Evidence of SFV infection includedseropositivity, proviral DNA detection and isola-tion of foamy virus. The infecting SFV originatedfrom all African green monkey (one person) andbaboons (three people). These infections have notas yet resulted in either disease or sexual transmis-sion, and may represent benign endpoint infec-tions. However, the potential risk inxenotransplantation remain unclear. Althoughthese viruses are the most cytopathic, syncytium-producing retroviruses for many cell types invitro, disease is seldom seen in the many speciesof primate they infect. However, mice transgenicSFV suffer neurodegeneration resembling amy-otrophic lateral sclerosis (Bothe et al., 1991), andvirus infection was evident in the brain of anorangutan which died with similar acute symp-toms (McClure et al., 1994). The few people whohave become infected with SFV do not exhibitany sign of disease, although they do exhibitantibody, responses and have viral genomes eas-ily, detected in blood by PCR, indicating thathumans can become infected by SFV, and in allprobability would do so following transplantationof primate tissue The effect of this infection in theimmunosuppressed xenograft recipient is notknown, but may be fatal considering the reportsin transgenic mice and orangutans (Bothe et al.,1991; McClure et al., 1994).

4. Herpesviruses

Herpesviruses have been shown to be transmit-ted by allografts. Corneas have been shown totransmit cytomegalovirus (CMV) and herpes sim-plex-virus (HSV). CMV seroconversion has beenreported in patients receiving skin grafts fromseropositive donors. Michaels et al. (1994)screened yellow baboons (Papio cynocephalus) forpresence of antibody to microbial agents (princi-pally viral) that may pose a significant risk of


infection. They detected antibodies to simian cy-tomegalovirus, simian agent 8 (HSV-equivalent ofbaboons) and Epstein–Barr virus in 97% of theanimals tested. Epstein–Barr virus transmissionthrough solid organ allograft transplantation inhumans has also been described (Cen et al., 1991).Another serilogical study in baboons indicatedpresence of antibody to CMV in 100% of theanimals tested, 90% tested positive to HSV-1, and70% to varicella virus (Van der Riet et al., 1987).The swine, which is being considered as one of theanimals ideal for obtaining organs for transplan-tation, in addition to expressing porcine endoge-nous retroviruses, also have a high incidence ofswine CMV, which has been shown to causefoetal demise (Edington et al., 1988).

Other herpes viruses such as the baboon orporcine CMV may be a concern to xenotransplantrecipients. The baboon CMV is endemic in ba-boon populations and therefore is a potentialcause of donor-associated disease after xenotrans-plantation. Human fibroblasts have been shownto be permissive for baboon CMV; isolates exhib-ited cytopathology characteristic of human CMVwhich is well-established as donor-transmitted af-ter allotransplantation (Michaels et al., 1997).Generally, CMV in vivo is considered to be ex-tremely species-specific. However, primary chim-panzee skin fibroblasts are permissive forreplication of the human Towne strain CMV(Perot et al., 1992), and another CMV strain(Colburn) has been isolated from a human brainbiopsy (Huang et al., 1978). Likewise, the humanherpes viruses such as herpes simplex virus type 1(HSV-1) and HSV-2, and varicella-zoster virus arecapable of infecting and causing disease and deathin non-human primates. Infection with humanEpstein–Barr virus (EBV) has been observed innon-human primates, but disease has not beenrecognised. Several other herpes viruses have beenrecovered from new world monkeys. All theseviruses produce mild or inapparent disease intheir natural hosts, but only the Herpes virussimiae (an a-herpesvirus) causes fatal diseaseswhen they cross the species lines into other hosts(Kalter and Heberling, 1990).

It has been shown that multiple strains of CMVcan be transmitted through solid organ transplan-

tation, and that new recombinant viral strains ofCMV arise readily through recombination of ex-isting strains (Chou, 1989). Recombinant virusescan be isolated when different viral strains arepassed through 20–25 passages in cell culture.The new strains were shown to have differentantigenic properties from the parent strain (Chou,1989). Evidence for presence of multiple latentstrains have also been found with herpes simplexvirus (HSV), whereby explant cultures of gangliaand nerve roots yielded multiple strains (Lewis etal., 1984). Recombinant strains arising from HSVhave been documented, and these recombinantstrains have been found to be lethal in vivo al-though the parent strains were avirulent (Javier etal., 1986). The possibility of such recombinantsarising as a result of xenotransplantation cannotbe ignored. There is no evidence at this time thatsuch recombination results in formation of patho-genic or infectious viruses in humans, but thepossibility exists (Auchincloss and Sachs, 1998).Herpesvirus simiae (B virus) was first isolated in1934 from the brain of a laboratory worker whodied after a bite from an apparently normal rhe-sus macaque monkey (Sabine and Wright, 1934),and since then, other cases of herpes simiae infec-tion have been reported. It appears that herpessimiae is the macaque monkey counterpart toherpes simplex in humans. Infection of the herpessimiae in its natural host is latent and benign. Itcauses self-limited recurrent oral or genital lesions(Kessler and Hilliard, 1990), but on transfer toman, it becomes fatal, causing acute ascendingmyelitis. Studies have shown that macaquecolonies, especially the rhesus monkey (Macacamulatta) may show a prevalence of approximately100% infectivity (Burnet et al., 1939), but thistends to be ignored by most investigators usingthis species for research (Kalter and Heberling,1990). Infection of macaques with the B virus islifelong with or without overt symptoms (the viruspersists in the ganglia). Shedding of the virusoccurs without any recognised stimulus, and againmay occur with or without overt indications ofinfection (Kalter and Heberling, 1990). The Bvirus can be a potential danger in xenotransplan-tation because although it is naturally infectiousonly for the Macaca species, it can also infect


humans and this infection is usually fatal, hencexenotransplants of nervous system tissues frommacaques becomes limited.

5. Other viruses

In the 1950s, millions of people were exposedto a monkey papovavirus, simian virus 40, whenthey received contaminated polio and adenovirusvaccines made in monkey kidney cells (Mortimeret al., 1981). Simian virus 40 is oncogenic inlaboratory animals, and sub-clinical infectionwas also documented in exposed persons byserum antibody and virus isolation studies.Luckily, so far, no increase in cancers has beendetected after 17–19 years of observation (Mor-timer et al., 1981). Bone allografts have trans-mitted hepatitis and human immunodeficiencyvirus. Heart valves have been implicated intransmitting Hepatitis B virus. Hepatitis C virustransmission has also been demonstrated vialiver, kidney and heart transplantations (Vin-centi et al., 1991). These incidences occurred be-fore sensitive diagnostic techniques wereavailable. Encephalomyocarditis, a diseasecaused by a picornavirus, is generally considereda murine infection but has a wide host rangethat includes baboons, pigs and humans (Kalterand Heberling, 1990). Disease outbreaks in pri-mates are often clinically evident, and animalsthat recover might have damaged myocardium,precluding their usefulness for cardiac transplantdonation. The simian haemorrhage fever (SHF)virus is also of considerable importance. Al-though transmission to humans has not beendemonstrated, the danger this virus poses to hu-mans need to be considered in xenotransplanta-tion. This virus is devastating to Macacaspecies, and is associated with three genera ofAfrican monkeys: Erythrocebus patas, Cercop-ithecus aethiops and Papio cynocephalus (Kalterand Heberling, 1990). The danger is due to thefact that it is difficult to diagnose the virus byserological tests as the animals succumb prior todevelopment of antibody, and the only availablediagnostic test (isolation of virus in MA-104cells) is not always successful. The only way ofavoiding this virus would be by utilising animals

which are raised in strict quarantined environ-ments.

Other viruses which need to be considered areemerging and re-emerging viruses. An emergingvirus is a term applied to a newly discoveredvirus, one that is increasing in incidence or withthe potential to increase in incidence. Manyviruses fit into this definition. HIV is theclearest example of a previously unknown virusthat has now produced one of the largest pan-demics in history. Recent advances have oc-curred in the identification and understanding ofnew hantaviruses in the Americas, causing anacute respiratory disease. The possible causalrole of human herpesvirus 8 in Kaposi’s sar-coma has gained support, whereas that of anewly discovered flavivirus in causing hepatitishas not been confirmed (Holland, 1998). A ma-jor advance has been evidence showing that thebovine spongiform encephalopathy agent is al-most certainly the cause of a new variant ofCreutzfeldt–Jacob disease (CJD). Although itscausation has for some time been ascribed to‘slow viruses’, the aetiology of Creutzfeldt–Ja-cob disease is currently thought to be due toprions, small proteinaceous infectious particlesthat have genetic encoding (Sternbach et al.,1997). CJD has been intensively monitored since1990 because of the risk BSE could pose topublic health. In 1995, two adolescents in theUK died of CJD, and through the early part of1996, other relatively young people had cases ofwhat became known as new variant CJD, whosetransmissible agent (indistinguishable from thatof BSE) is responsible for 26 cases in the UKand one in France (Pattison, 1998). Areas ofconcern include how many cases will appear inthe future and whether or not use of humanblood and blood products may cause a secondcycle of human infections. Although new virusesare discovered almost yearly (e.g. Australian batlyssavirus), other ‘older’ viruses (e.g. dengue) arere-emerging, infecting millions of people everyyear with significant mortality (Holland, 1998).Most of these viruses can be tested and detectedin the laboratory, before a xenograft is trans-planted, but there is a lot which is not knownabout these viruses, such as their prevalence, in-


cubation period and the sensitivity of the test kitsused. The possibility of a false negative result, andthe lack of knowledge on the effects these viruseswould have when transmitted to humans makes itnecessary to impose limitations on xenotransplan-tations until more information is available.

6. Summary

Substantial progress has been made on the im-munological problems of xenotransplantation.The risks of infectious disease transmitted fromgraft to recipient, and henceforth to the new hostpopulation, remains a topic of lively debate. Theknown infectious pathogens of the donor speciescan be monitored and largely eliminated throughthe specific breeding of pathogen-free herds. Un-fortunately, this will not prevent transmission ofendogenous retroviruses, for which we do notscreen and for which the risk of disease is notknown. There is the possibility that unknown,often latent infections which are asymptomatic intheir natural host, could cause disease in thexenograft recipient. It is possible that an animalvirus could combine with a human virus, creatinga more pathogenic and virulent microbe.Zoonotic and xenozoonotic diseases are not re-mote possibilities, they exist in various forms andcome from various sources. The nature of trans-plantation requires the suppression of the immunesystem resulting in opportunistic infections. Evenif procedures to avoid increased levels of immuno-suppression to the recipient were successful, risksto third parties, whose immune systems, for vari-ous reasons, may, not be equipped to fight off theinfection, would remain. However, the number ofxenotransplantations may increase despite themany concerns about the likelihood of spreadingknown and unknown infectious agents, since thedemand for donor organs is so high that it cannever be satisfied by the human donor pool. Theability to cross species lines through xenotrans-plantation has the potential to save lives whenhuman donor organs are unavailable, but it isimportant to consider the possible complicationsof cross-species transmission of infection beforethey occur.

References

Allan, J.S., Broussard, S.R., Michaels, M.G., et al., 1998.Amplification of simian retroviral sequences from humanrecipients of baboon liver transplants. AIDS Res. Hum.Retrovir. 14, 821–824.

Akiyoshi, D.E., Denaro, M., Zhu, H., Greenstein, J.L., 1998.Identification of full length cDNA for an endogenousretrovirus of the miniature swine. J. Virol. 72, 4503–4507.

Auchincloss, H., Sachs, D.H., 1998. Xenogeneic transplanta-tion. Ann. Rev. Immunol. 16, 433–470.

Bach, F.H., 1998. Xenotransplantation: problems andprospects. Ann. Rev. Med. 49, 301–310.

Benveniste, R.F., Lieber, M.M., Livingstone, D.M., Sherr,C.J., Todaro, G.J., 1974. Infectious C-type virus isolatedfrom a baboon placenta. Nature 248, 17–20.

Benveniste, R.E., Morton, W.R., Clark, E.A., et al., 1988.Inoculation of baboons and macaques with SIVmne, aprimate lentivirus closely related to HIV-2. J. Virol. 62,2091–2101.

Bergelson, J.M., Mohanty, J.G., Crowell, R.L., St. John, N.F.,Lublin, D.M., Finberg, R.W., 1995. Coxsackievirus B3adapted to growth in RD cells binds to decay acceleratingfactor (CD55). J. Virol 69, 1903–1906.

Bothe, K., Aguzzi, A., Lassman, H., Rethwilm, A., Horak, I.,1991. Progressive encephalopathy and myopathy in trans-genic mice expressing human foamy virus genes. Science253, 555–557.

Brennan, C.A., Yamaguchi, J., Vallari, A.S., Hickman, R.K.,Devare, S.G., 1997. Genetic variation in human im-munodeficiency virus type-2: identification of a uniquevariant from human plasma. AIDS Res. Hum. Retrovir.13, 401–404.

Burnet, F.M., Lush, D., Jackson, A.V., 1939. The relationshipof herpes and B viruses: immunological and epidemiologi-cal considerations. Austr. J. Exp. Biol. Med. Sci. 17,41–51.

Cen, H., Breinig, M.C., Atchinson, R.W., Ho, M., McKnight,J.L.C., 1991. Epstein–Barr virus transmission via donororgans in solid organ transplantation: polymerase chainreaction and restriction fragment length polymorphismanalysis of IR2, IR3 and IR4. J. Virol. 65, 976–980.

Centres for Disease Control (CDC) and Prevention Update(1992). Seroconversion to simian immunodeficiency virusin two laboratory workers. MMWR, 678.

Chapman, L.E., Folks, T.M., Salomon, D.R., Patterson, A.P.,Eggerman, T.E., Noguchi, P.D., 1995. Xenotransplanta-tion and xenogenetic infections. New Engl. J. Med. 333,1498–1501.

Chen, Y.M.A., Jang, Y.J., Kanki, P.J., et al., 1994. Isolationand characterisation of simian T-cell leukaemia virus typeII from New World monkeys. J. Virol. 68, 1149–1157.

Chou, S., 1989. Reactivation and recombination of multiplecytomegalovirus strains from individual organ donors. J.Infect. Dis. 160, 11–15.

Coffin, J., 1984. Endogenous viruses. In: Weiss, R., Teich, N.,Vermus, H., Coffin, J. (Eds.), Molecular Biology of Tu-


mour Viruses: RNA Tumour Viruses, second ed. ColdSpring Harbour Press, New York, pp. 1109–1203.

Cooper, D.K.C., 1993. Xenografting: how great is the clinicalneed? Xenotransplantation 1, 25–26.

Cooper, D.K.C., 1996. Xenotransplantation — state of theart. Front. Biosci. 1, D248–265.

Desrosiers, R.C., 1990. A finger on the missing link. Nature345, 288.

Eastlund, T., 1995. Infectious disease transmission throughcell, tissue and organ transplantation: reducing the riskthrough donor selection. Cell Transplant. 4, 455–477.

Edington, N., Wrathall, A.E., Done, J.T., 1988. Porcine cy-tomegalovirus (PCMV) in early gestation. Vet. Microbiol.17, 117.

Fenjves, E.S., Yao, S.N., Kurachi, K., Taichman, L.B., 1996.Loss of expression of a retrovirus-transduced gene in hu-man keratinocytes. J. Invest. Dermatol. 106 (3), 576–578.

Flugel, R.M., 1991. Spumaviruses: a group of complex retro-viruses. J. AIDS 4, 739.

Fultz, P.N., Gordon, T.P., Anderson, D.C., McClure, H.M.,1990. Prevalence of natural infection with simian im-munodeficiency virus and simian T-cell leukaemia virustype I in a breeding colony of sooty mangabey monkeys.AIDS 4, 619–625.

Gao, F., Yuc, L., Robertson, D.L., et al., 1994. Geneticdiversity of human immunodeficiency virus type-2: evi-dence for distinct sequence sub-types with differences invirus biology. J. Virol. 68, 7433–7447.

Gao, F., Yue, L., White, A.T., et al., 1992. Human infectionby genetically diverse SIVsm-related HIV-2 in west Africa.Nature 358, 495–499.

Groth, C.G., Korsgren, O., Tibell, A., et al., 1994. Transplan-tation of porcine foetal pancreas to diabetic patients.Lancet 344, 1402–1404.

Hayami, M., Ido, E., Miura, T., 1994. Survey of simianimmunodeficiency virus among non-human primate popu-lations. Curr. Top. Microbiol. Immunol. 188, 1–18.

Heneine, W., Switzer, W.M., Sandstrom, P., et al., 1998.Identification of a human population infected with simianfoamy viruses. Nat. Med. 4, 403–407.

Hirsch, V.M., Johnson, P.R., 1992. Pathogenesis of experi-mental SIV infection. Semin. Virol. 3, 175–183.

Holland, D.J., 1998. Emerging viruses. Curr. Opin. Pediatr.10, 34–40.

Homma, T., Kanki, P.J., King, N.W., et al., 1984. Lymphomain macaques: association with virus of HTLV-1 family.Science 225, 716–718.

Huang, E., Kilpatrick, B., Lakeman, A., Alford, C.A., 1978.Genetic analysis of a cytomegalovirus-like agent isolatedfrom a human brain. J. Virol. 26, 718.

Ishikawa, K., Fukasawa, M., Tsujimoto, H., et al., 1987.Serological surveys and virus isolation of simian T-cellleukaemia/T-lymphotrophic virus type I (STLV-I) in non-human primates in their native countries. Int. J. Cancer 40,233–239.

Javier, R.T., Sedarati, F., Stevens, J.G., 1986. Two avirulentherpes simplex viruses generate lethal recombinants invivo. Science 234, 746–748.

Jin, M.J., Rogers, J., Philips-Conroy, J.E., et al., 1994. Infec-tion of a yellow baboon with simian immunodeficiencyvirus from west African monkeys: evidence for cross-spe-cies transmission in the wild. J. Virol. 68, 8454–8460.

Johnson, P.M., Lyden, T.W., Mwenda, J.M., 1990. Endoge-nous retroviral expression in the human placenta. Am. J.Reprod. Immunol. 23, 115–120.

Kalter, S.S., Heberling, R.L., 1990. Priniate viral diseases inperspective. J. Med. Primatol. 19, 519–535.

Kanki, P.J., Essex, M., 1988. Simian T-lymphotrophic virusesand related human viruses. Vet. Microbiol. 17, 309.

Karpas, A., 1990. Origin and spread of AIDS. Nature 348,578.

Kessler, M.J., Hilliard, J.K., 1990. Sero-prevalence of B virusantibodies in a naturally formed group of Rhesusmacaques. J. Med. Primatol. 19, 155.

Lehrman, S., 1995. AIDS patient given baboon bone marrow.Nature 378, 756.

Lewis, M.E., Leung, W.C., Jeffrey, V.M., Warren, K.G., 1984.Detection of multiple strains of latent herpes simplex virustype I within individual human hosts. J. Virol. 52, 300–305.

Makowka, L., Cramer, D.V., Hoffman, A., 1995. The use ofpig liver xenograft for temporary support of a patient withfulminant hepatic failure. Transplant 59, 1654–1659.

Martin, U., Steinhoff, G., Kiessig, V., et al., 1998. Porcineendogenous retrovirus (PERV) was not transmitted fromtransplanted porcine endothelial cells to baboons in vivo.Transpl. Int. 11, 247–251.

Martin, U., Kiessig, V., Blusch, J.H., et al., 1998. Expressionof pig endogenous retrovirus by primary porcine endothe-lial cells and infection of human cells. Lancet 3512, 692–694.

Marx, P.A., Li, Y., Lerche, N.W., et al., 1991. Isolation of asimian immunodeficiency virus related to human im-munodeficiency virus type-2 from a west African pet sootymangabey. J. Virol. 65, 4480–4485.

McClure, M.O., Bieniasz, P.D., Schultz, T.F., et al., 1994.Isolation of a new foamy retrovirus from orangutans. J.Virol. 68, 7124–7130.

Meng, X.J, Purcell, R.H., Halbor, P.G., et al., 1997. A novelvirus in swine is closely related to the human hepatitis Evirus. Proc. Natl. Acad. Sci. USA 94, 9860–9865.

Michaels, M.G., Alcendor, D.J., St. George, K., et al., 1997.Distinguishing baboon cytomegalovirus from human cy-tomegalovirus: importance for xenotransplantation. J. In-fect. Dis. 176, 1476–1483.

Michaels, M.G., McMichael, J.P., Bradsky, K., et al., 1994.Screening donors for xenotransplantation: the potential forxenozoonoses. Transplant 57, 1462–1465.

Montefiori, D.G, Cornell, R.J., Zhou, J.Y., Zhou, J.T.,Hirsch, V.M., Johnson, P.R., 1994. Complement controlproteins CD46, CD55 and CD59 as common surface con-stituents of human and simian immunodeficiency virus andpossible targets for vaccine protection. Virology 205, 82–92.


Mortimer, E.A., Lepow, M.L., Gold, E., Robbins, F.C., Bur-ton, G.J., Fraumeni, J.F., 1981. Long-term follow-up ofpersons inadvertently inoculated with SV40 as neonates.New Engl. J. Med. 305 (25), 1517–1518.

Mwenda, J.M., 1994. Possible biological functions for theexpression of endogenous retroviral gene products in thehuman placental tissues. Cell. Mol. Biol. 40, 105–109.

Noda, Y., Ishikawa, K., Sasagawa, A., et al., 1986. Haemato-logic abnormalities similar to preleukaemic state of adultT-cell leukaemia disease in African green monkeys natu-rally infected with simian T-cell leukaemia virus. Jpn. J.Cancer Res. 77, 1227–1234.

Ohta, Y., Masuda, T., Tsujimoto, H., et al., 1988. Isolation ofsimian immunodeficiency virus from African green mon-keys and seroepidemiologic survey of the virus in variousnon-human primates. Int. J. Cancer 41, 115–122.

Owusu, S.K., 1991. Origin and spread of AIDS. Nature 350,184.

Patience, C., Patton, G.S., Taketichi, Y., et al., 1998. Noevidence of pig DNA or retroviral infection in patientswith short-term extracorporeal connection to pig kidneys.Lancet 352, 699–701.

Patience, C., Takeuchi, Y., Cosset, F.L., Weiss, R.A., 1998.Packaging of endogenous retroviral sequences in retroviralvectors produced by, murine and human packaging cells. J.Virol. 72, 2671–2676.

Patience, C., Takeuchi, Y., Weiss, R.A., 1997. Infection ofhuman cells by an endogenous retrovirus of pigs. Nat.Med. 3, 282–286.

Pattison, S.J., 1998. The emergence of bovine spongiformencephalopathy and related diseases. Emerg. Infect. Dis. 4,390–394.

Perot, K., Walter, C.M., Spaete, R.R., 1992. Primary chim-panzee skin fibroblast cells are fully permissive for humancytomegalovirus replication. J. Gen. Virol. 73, 3281.

Puddu, P., Locardi, C., Sestili, P., et al., 1991. Human im-munodeficlency virus (HIV)-infected tumour xenografts asan in vivo model for anti-viral therapy: role of alpha/betainterferon in restriction of tumour growth in nude miceinjected with HIV-infected U937 cells. J. Virol. 65, 2245–2253.

Rother, R.P., Foder, W.L., Springhorn, J.P., et al., 1995. Anovel mechanism of retrovirus inactivation in humanserum mediated by anti-a-galactosyl natural antibody. J.Exp. Med. 182, 1345–1355.

Reiprich, S., Gundlach, B.R., Fleckenstein, B., Uberla, K.,1997. Replication-competent chimeric lenti-oncovirus withexpanded host cell tropism. J. Virol. 71, 3328–3331.

Sabine, A.B., Wright, A.M., 1934. Acute ascending myelitisfollowing a monkey bite, with isolation of a virus capableof reproducing the disease. J. Exp. Med. 59, 115–136.

Simonds, R.J., Holmberg, S.D., Hurwitz, R.L, et al., 1992.Transmission of human immunodeficiency virus type 1from a seronegative organ and tissue donor. New Engl. J.Med. 326, 726–732.

Sternbach, G., Dibble, C.L., Varon, J., 1997. FromCreutzfeldt–Jakob disease to the mad cow epidemic. J.Emerg. Med. 15, 701–705.

Stoye, J.P., 1997. Proviruses cause potential problems. Nature386, 126–127.

Takeuchi, K., Ohoka, H., Yokoyama, M., Iwata, H,Takeuchi, M., 1996a. A technique of urinary bladdertransplantation in the rat. Transplant Proc. 28, 1978–1979.

Takeuchi, Y., Porter, C.D., Strahan, K.M., et al., 1996b.Sensitisation of cells and retroviruses to human serum bya(1-3)-galactosyltransferase. Nature 379, 85–88.

Taruscio, D., Mantovani, A., 1998. Fluman endogenous retro-viral sequences: possible roles in reproductive physio-pathology. Biol. Reprod. 59, 713–724.

Tsujimoto, H., Noda, Y., Ishikawa, K., et al., 1987. Develop-ment of adult T-cell leukaemia-like disease in Africangreen monkeys associated with clonal integration of simianT-cell virus type I. Cancer Res. 47, 269–279.

Urnovitz, H.B., Murphy, W.H., 1996. Human endogenousretrovir-uses: nature, occurrence and clinical implicationsin human disease. Clin. Microbiol. Rev. 9, 72–99.

Van der Riet, F., Human, P.A., Cooper, D.K.C., et al., 1987.Virological implications of the use of primates in xeno-transplantation. Transplant. Proc. 19, 4068–4069.

Vincenti, F., Weber, P., Kuo, G., et al., 1991. Hepatitis Cvirus in cadaver organ donors: prevalence and risk oftransmission to transplant recipients. Transplant. Proceed.23 (5), 2651–2652.

Weiss, R.A., 1988. A virus in search of a disease. Nature 333,497.

Weiss, R.A., 1996. Foamy viruses bubble on. Nature 381, 201.Weiss, R.A., 1998. Transgenic pigs and virus adaptation.

Nature 391, 327–328.Wilkinson, D.A., Mager, D.L., Leong, J.C., 1994. Endogenous

human retroviruses. In: Levy, J. (Ed.), Retroviridae, vol. 3.Plenum Press, New York.

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potential risks of viral infections in xenotransplantation

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