ILAR Journal Online, Volume 37(1) 1995: Perspectives on Xenotransplantation

Online Issues

<< All Back-issues

<< This Issue's Table of Contents

ILAR Journal V37(1) 1995
Perspectives on Xenotransplantation

Xenograft Transplantation and the Infectious Disease Conundrum
Jonathan S. Allan

Jonathan S. Allan, D.V.M. is a scientist in the Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas.

INTRODUCTION

Transplant surgeons and AIDS clinicians are on the verge of implementing a host of new procedures that will revolutionize transplantation and adoptive cell transfer techniques in a quest for cures to such diverse medical conditions as heart disease and AIDS. Just as gene therapy is expected to directly impact inherited diseases, new advances in immunosuppressive drug combinations and new discoveries in our understanding of the fundamental processes of immune tolerance have led to the real possibility of engineering tissue and cell transplants from other living species such as baboons and pigs into humans (xenogeneic transplantation) (Starzl and others 1994). At the same time, interest in emerging viruses as a discipline for virologists and infectious disease specialists has surfaced, and it appears that these two fields may be on a collision course at the present moment (Michaels and Simmons 1994; Allan 1994).

Several recent reviews have focused attention on the notion that new human diseases continue to present danger with the appearance of new viruses, a consequence of cross-species transmission from animal reservoirs to humans (zoonoses) (Morse 1993; Morse and Schluederberg 1990; Murphy and Nathanson 1994; Murphy 1994). A zoonosis is generally defined as an infection of one or relatively few humans with an animal virus without necessarily establishing itself in that population. The real threat of an emerging virus is when, or if, it is transmitted from one human to another, and this is where the danger lies with xenotransplantation. Numerous examples of the emergence of human viral diseases are available but the most studied culprit and one that reaches deep into the consciousness of most Americans is AIDS. In this review, I will try to put into perspective, in some cases through example, the reasons why the risk to the human population from xenogeneic transplantation is unacceptable.

We have had ample historical warnings of the dangers associated with animal-to-human zoonoses yet we continually ignore these signals. Isn't it ironic that the most notorious infectious disease known to humankind appears to have arisen through inadvertent transmission from an African nonhuman primate. Yet there are those who now want to use tissues from African monkeys in an attempt to cure AIDS, in my opinion, without sufficient forethought as to the consequences and risk to the human population of such procedures. It is also prophetic that we are having to revisit the plague with recent headlines decrying the exodus of 400,000 people from a city in India as panic sets in over the mounting death toll from pneumonic plague. Also known as the Black Plague, Yersinias pestis was responsible for the death of one-third of the total population of Europe in the late thirteenth and early fourteenth century (Morse 1993). If we think we have eradicated most forms of pestilence from our civilization, then it is time to think again, for we will continue to be bombarded either by reemerging diseases, as is the case with the plague, or by newly emerging diseases such as AIDS.

HISTORICAL PERSPECTIVES

Recently, there has been an explosion of interest surrounding emerging viral diseases. To put this into perspective, public health agencies are devoting considerable, though sometimes inadequate, resources toward epidemiological surveillance in preparing to identify, characterize, and contain new viral epidemics in humans. Instances where humans are in greater contact with animal species, as is seen in the destruction of the rain forests, allow for far greater risks in transmitting new viruses from rodents and monkeys to humans. This has been observed with the emergence of human monkeypox, a virus originating in African monkeys, which led to 10% case fatality rate in humans (Fenner 1993). In West Africa, the reemergence of yellow fever generally coincides with high viral burdens in monkey reservoirs even though the virus is transmitted by insect vectors (Monath 1994). Past successes in controlling new emerging diseases are proudly recounted, such as tracking down the Hantavirus outbreak in the Southwest United States (Ion-Nedelcu and others 1994). Fortunately, this newly identified strain of Hantavirus is a zoonotic disease resulting from the inhalation of soil and other material contaminated with rodent urine and is apparently not easily transmitted from person to person (Hjelle and others 1994). The infection is usually associated with an acute febrile illness and rapid recovery or death from pneumonia, which also severely reduces the chances of transmission to another person.

Another example of the public health agencies ability to successfully intercede in cases of zoonotic transmission of disease was the identification and containment of a recent Ebola-like virus (Reston Virus) outbreak in a macaque colony in Virginia for which the virus received its name (Peters and others 1994; Jahrling and others 1990). A second virus, simian hemorraghic fever virus (SHF), was also found in the cynomolgus macaques, confusing the initial efforts to identify the etiologic agent (Dalgard and others 1992). The SHF virus is generally associated with cross-species transmission from an African monkey to macaques, however, seroepidemiologic studies revealed that many monkey species had antibodies reactive with Ebola viruses so it is uncertain what events are necessary for Ebola-associated disease. Nevertheless, the disease spread quickly resulting in the deaths of many animals. Curiously, serological studies of four of the staff members at the facility indicated that humans were infected with the Reston virus. Luckily, no disease was observed and there were apparently no human-to-human transmissions.

In both of the above cases, the major reason that a new emerging disease did not materialize had less to do with human intervention than with the characteristics of the virus. In these cases, virus infection was apparently self-limiting and for the Reston virus not clinically significant to humans. However, the most serious zoonotic infections are ones that establish themselves in humans but leave no animal signature, and thus the false impression of a newly evolved human disease. Many animal viruses that pose a risk for initiating new diseases in humans generally cause no overt damage to their natural host reservoir so that identification of potential pathogens from those animals is not possible. What seems to be missing in all of these surveillance efforts is the fact that we are not devoting our efforts towards preventing the initial introduction of these new viruses into humans. Once the virus has silently found its way into one human sentinel case, there can be little chance of reversing the process. As Stephen Morse put it, "We might consider the emergence of new viruses as a two-step process, the first step being the introduction of the virus into a human population, and the second step dissemination within the population" (Morse 1994). Xenotransplantation may well accomplish the first step in the process.

Unfortunately, there are also many instances in which the outcome has not been a success story. Herpes B virus is a common oral and genital infection of macaques with symptoms similar to herpes simplex virus infection in humans (Weigler 1992). In a limited number of cases, humans infected with this virus develop a rapidly fatal neurologic disease. Since the advent of acyclovir therapy, a few individuals have survived their infections, and in one case, an infected person appears to have infected his spouse. However, further spread of herpes B virus has not been observed (Holmes and others 1990). Again, contact with primates can lead to fatal consequences, yet the difficulty in transmission from person to person naturally limits this disease to a few individuals; generally those whose occupation involves frequent contact with macaques. It should be noted that since we now have developed therapies to control B virus infection in humans, in one sense we may have increased the risk to the overall population by promoting the survival of the virus in its human host.

Another example that illustrates the potential for monkey-to-human transmission through human intervention involves the pioneering work of the poliovirus vaccine researchers. A recent expose in the Rolling Stone accused Dr. Koprowski, whose clinical vaccine trials in Africa and Poland were instrumental in the development of the live attenuated poliovirus vaccine, of being responsible for creating the AIDS epidemic (Curtis 1992). The crux of the story centered upon the idea that the poliovirus used in the vaccine had been grown on monkey cells and that these cells may have harbored immunodeficiency viruses that then became the progenitor to the human AIDS virus. Common sense however, tells us that this could not have been the case (Koprowski 1992). First, the monkey kidneys used in making the primary cell cultures were from Asian macaques, which do not carry an SIV-like virus in the wild. Second, the virus does not replicate in kidney cells. Third, the human AIDS virus, HIV-1 virus, is most closely related to the chimpanzee virus SIVcpz, which is therefore most likely responsible for the original infections in humans (Peeters and others 1992). Nevertheless, these types of stories continue to surface in regard to the origins of AIDS. One cautionary note, although the early vaccine preparation were generally prepared on macaque cell lines, until very recently, most poliovirus seed stocks were propagated in primary kidney cultures from African green monkeys. Seed stocks refer to those virus stocks that are generated every few years and are used as a source to expand and propagate virus for large scale vaccine production. In most cases, these African monkeys were not tested for SIVagm infection, yet 40-50% of African green monkeys carry SIV in the wild (Kanki and others 1985a). Again, no evidence of an SIVagm-like virus has been observed in humans, and SIVagm does not replicate in kidney cells.

The poliovirus vaccines did in fact lead to inadvertent exposure of millions of people to another monkey virus, SV40, a DNA virus that is known to transform human cells in culture and has the capacity to induce cancer in experimental animals (Shah and Nathanson 1976). SV40 was recovered from the macaque kidney cells along with poliovirus. In one 20-year follow-up study, no evidence of any link to cancer caused by SV40 in these vaccines was uncovered (Mortimer and others 1981). Recently, however controversy resurfaced in regard to SV40 contaminated poliovirus vaccine lots. In a new study, a significant number of mesotheliomas contained viral DNA (29 of 48 cases), which, of any of the known papovaviruses, most closely resembled SV40 (Carbone and others 1994). While preliminary in scope, these findings do suggest that monkey viruses may play a role in human cancer and will require further analysis to resolve this issue.

The poliovirus vaccine efforts led to yet another serious infectious disease outbreak. In 1967, 31 cases of an acute hemorraghic disease afflicted laboratory personnel in Germany and Yugoslavia, which included seven deaths (Kissling and others 1968). The illness was a direct result of exposure of laboratory workers to African green monkey kidneys being used to propagate poliovirus. It seems that the African green monkeys harbored a new virus which was later identified as Marburg virus, a member of the filovirus group. A similar outbreak caused by an antigenically related filovirus, Ebola, was seen in 1976 in Africa, which led to the deaths of over 400 people living in Central Africa with a 90% mortality rate (WHO 1978). The Ebola virus was originally thought to be linked to African monkeys, yet it is still uncertain how the African monkeys contracted the infection since serologic studies have not indicated a primate reservoir. The acute and lethal nature of these viral infections was an important factor in containing the infection because infected individuals could be quarantined thus limiting contact and further spread of infection. It is still uncertain if baboons harbor filoviruses, although one report suggests that Chacma baboons may carry serologically related viruses (Lecatsas and others 1992).

What these stories do tell us is that we have been remarkably lucky that our efforts to cure one disease have not led to more deadly consequences in spite of our repeated encounters with unexpected microbial agents. These types of cases also serve to illustrate that one cannot know what the consequences will be of introducing a new virus into an unnatural host (humans). A virus that seems ubiquitous in nature and induces little or no pathology in its natural host may under the proper conditions wreak havoc in a foreign host. Of course many of these infections may become inapparent, or abortive in humans. Monkeys are genetically closely related to humans and thus the receptors for various virus types may be highly conserved. Indeed, most mon-key viruses are isolated and characterized by their growth on human cell cultures. However, it is impossible to predict what effect introduction of a "non-pathogenic" animal virus into humans will have.

While monkey-to-human infections may result in new epidemics, human-to-human transplantations and blood transfusions have routinely led to morbidity and mortality. From herpesviruses to hepatitis and AIDS, our attempts to save lives have had isolated but disastrous consequences. At least six cases of rabies have been reported in humans receiving corneal transplants from cadavers, where the individuals were only later determined to have died from rabies (Houff and others 1979). In 1974, Creutzfeldt-Jakob disease, a slowly progressive and transmissible dementia was also acquired following corneal transplantation (Duffy and others 1974). The most notorious cases of human error are those related to AIDS in the early 1980s. Hemophiliacs and blood transfusion recipients became inadvertently infected with HIV when receiving blood and blood products. Upwards of 90 percent of all hemophiliacs and transfusion recipients in this country and elsewhere became infected within just a few short years and many have since died (Peterman and others 1987). The controversy surrounding blood transfusions and acquired HIV infection continues in the press with administrators from blood centers in France imprisoned for not moving quickly in testing blood preparations because a French test kit was not yet on the market, while an American commercial kit was already available. It has been estimated that over 12,000 transfusion recipients became infected with HIV before HIV antibody testing of the U.S. blood supply was instituted. In addition, many human transplant recipients were inadvertently infected with HIV-1 before testing was instituted in the early 1980s. One can well imagine a similar scenario emanating from just a few successful transplant recipients, with donors and recipients participating in the grand experiment of life, the donor providing not only a viable organ but also all of its resident microbes.

It should be mentioned that an important reason for using baboon tissue is not because of the shortage of human organs but that the baboon is resistant to some known human viral infections such as the hepatitis B virus. This virus continues to be a major problem in liver transplant recipients (Hollinger 1990). Some of these patients are in need of a new liver precisely because their own has been destroyed by hepatitis viruses. Implanting a new human liver generally leads to the same consequence in chronic carriers where the donated liver also becomes infected and is destroyed. Baboon livers are seen as a way around this infectious disease problem due to species restriction in hepatitis virus replication. Similarly, baboon bone-marrow cells are being considered as a last resort in AIDS patients who have lost their CD4 T-cell subset population and are in the late stages of AIDS. Studies in my laboratory indicate that baboon CD4 T cells resist infection with HIV-I (Allan unpublished data). What this means is that if one can generate chimerized bone marrow where the baboon immune cells can function normally in a human host, then one can essentially reconstitute a functional chimeric baboon-human immune system with natural resistance to HIV conferred by baboon T cells. Success in rodent models has laid the foundation for these studies (Ildstad and others 1992), although a single attempt at baboon-to-human bone marrow transplantation has failed (Ricordi and others 1994), and graft-versus-host disease is still a concern for those studies.

Obviously, some baboon viruses will not be transmitted to humans due to constraints either at the level of viral entry or during their replication. However most, if not all, of the known baboon viruses have been shown to grow in human cell lines, so there is no great leap of faith in surmising that viruses will set up shop in a new human host. Whether the transplanted material is liver or bone marrow, the sheer numbers and variety of cell types that will be introduced is phenomenal and will likely include several microbes as well. There may be less enthusiasm for using organs from phylogenetically more distantly related species such as swine for human transplantation, but the distance also belies the fact that viruses carried by pigs are theoretically less likely to be infectious to humans due to a higher degree of variation in cellular receptors used by these viruses, whereas the close genetic relationship between baboons and humans enhances the possibility of transmitting animal viruses to humans.

The lessons being learned from the AIDS epidemic are also relevant to this discussion. The human viruses, HIV-1 and HIV-2, share a great amount of homology with chimp and mangabey simian immunodeficiency virus (SIV) isolates, respectively (Myers and others 1992). It is generally accepted that cross-species transmission of SIV viruses to humans were the sources for the emergence of human AIDS. No one will ever know who was first infected and when, yet most epidemiological studies point to the late 1950s for the onset of HIV- 1 and the early 1970s for HIV-2. Interestingly, an animal model was discovered by coincidence soon after HIV was identified. At the New England Regional Primate Research Center in Southborough, Massachusetts, a severe immunodeficiency-like disease was observed in a few macaques that were involved in studies to understand the pathogenesis of STLV, a retrovirus that had been identified with lymphoid cancers in macaques (Daniel and others 1985; Kanki and others 1985b). Careful analysis led to the discovery of a related but distinct virus from HIV called SIVmac. This virus was demonstrated to induce classic AIDS like disease including a loss in CD4+ T cells in Asian macaques (Letvin and others 1985). Soon after, seroepidemiologic studies provided a link to African green monkeys and a related virus was isolated and designated SIVagm (Kanki and others 1985a). Unlike SIV in macaques, African green monkeys showed no signs of illness when naturally infected or by experimental infection. A direct link between SIVmac and a natural African monkey reservoir was determined at both the Yerkes Regional Primate Research Center in Atlanta, Georgia and the Tulane Regional Primate Research Center in Covington, Louisiana (Murphey-Corb and others 1986; Fultz and others 1986). Another African monkey, the sooty mangabey, had high prevalence rates to SIVsm, and genetic analysis revealed a close relationship to the macaque virus, which strongly implicated the mangabey virus as the cause of the macaque outbreak (Hirsch and others 1989). A total lack of SIV infection in the wild for macaques supports the possibility of cross-species transmission and is consistent with the theory that unnatural host species are likely to be more susceptible to disease from infection with a new virus.

Coincidentally, a second human virus (HIV-2) was found in West Africans and was also highly related to the mangabey virus (Barin and others 1985;Clavel and others 1986). It is interesting that the sooty mangabey's geographic distribution in nature is limited to West Africa which is precisely where HIV-2 is found. This story also points out another important aspect to new viral diseases in terms of their unpredictable nature for causing disease. Whereas HIV-1 is considered an important health problem due to its high morbidity and mortality, it appears that HIV-2 is much less pathogenic, and may not be transmitted as easily as HIV-1 (Marlink and others 1994). One can speculate that the relative replication rates for these viruses differ substantially in their respective human hosts, which might account for this variation in pathogenesis. There are several ways that this dispersion may have arisen. First, HIV-1 has been in the human population considerably longer than HIV-2 and has had a greater adaptive advantage. Alternatively, HIV-1 may simply be intrinsically more pathogenic while HIV-2 is not likely to reach the same levels of replication in humans.

The significance of these studies in relation to this discussion is that it is apparent that African monkeys have been infected with their own virus types for perhaps thousands of years. This can be inferred because the relative phylogeny for the SIVs parallels the phylogeny of the monkeys. For example, there are four distinct SIVagm viruses that are related to each other to the same extent that the monkeys are related (Allan and others 1991). This suggests that the viruses have co-evolved and then diverged along with their respective hosts.

While these viruses have probably reached a delicate balance with the natural host, the existence of these viruses was not discovered until after many thousands of humans began developing a new clinical entity called AIDS. In some ways, the medical community was lucky, the virus grew in CD4 T cells and T-cell growth factor (IL-2) had only recently been discovered allowing for the cultivation in vitro of the HIV in primary lymphocyte cultures. Also, the tropism of the virus was quickly determined rather easily because commercial antibodies used to type T-cell subsets also blocked HIV infection in culture (Dalgleish and others 1985). Imagine the difficulties that would have been encountered had the receptor not been previously identified. Seroepidemiologic studies are still incomplete but it is likely that there are about 30 distinct SIV types harbored in African monkeys, and some of these viruses may have the potential of becoming a new human AIDS variant (Myers and others 1992; Allan 1992). It is important to keep this in mind in discussing monkey-to-human transplants for AIDS.

Direct evidence for the transmissibility of monkey SIVs to humans comes from a recent report on the accidental infection of two laboratory workers with the SIVmac virus (Khabbaz and others 1994). While not certain, it appears that these people were exposed while handling large quantities of infectious tissue culture fluids. Seroconversion was evident, although initial attempts to isolate the virus have failed. It is probable that accidental infection with SIVmac might also require sufficient replication and adaptation before host-specific disease or transmission among close contacts is manifested (Essex 1994).

BABOON VIRUSES TRANSMISSIBLE TO HUMANS

One must also keep in mind that the greatest risk of xenotransplantation to humans comes from viruses that are waiting to be discovered. In general, viruses from newly emerging diseases are only identified once the target population has been significantly affected. That is, until the human disease is evident there is no reasonable means for evaluating potential pathogens currently harbored by nonhuman primates. While numerous baboon viruses have been identified, it is not unreasonable to suggest that there may be just as many viruses that have yet to be discovered and are as much of a threat as the established ones. It should be noted that detailed analysis of the types of baboon viruses in nature is still only a poor estimation. Most of these viruses were discovered in the late 1960s or early 1970s, and their detailed relationship to other mammalian viruses is still slowly evolving (Kalter and Heberling 1990; Barahona and others 1974). Very little basic research has focused on the characterization of baboon viruses within the last twenty years. In fact, the assays available for detecting some of these viruses and for their isolation have not changed substantially over the years. Furthermore, some of the commercial assays to detect antibodies to viral antigens may not be optimal in detecting baboon viruses. For example commercial ELISA (enzyme-linked immunosorbent assay) kits are sometimes used to screen baboons for antibodies to STLV, a retrovirus closely related to the human counterpart HTLV. However, detailed studies to determine the sensitivity and specificity of the baboon response for detection with this kit have not been fully elucidated. For other viruses, even less is known about the serological utility of baboon antibodies for viral analysis. Until more detailed studies are conducted to assess the validity of these assays it is uncertain whether most animals are truly virus-negative for some of the pathogens for which they are being screened. In addition, there are circumstances where an animal may be viremic yet lack detectable antibodies to that virus either because of a newly acquired infection or a host-specific block in generating antiviral antibodies. One must then contend with these possibilities before embarking on these transplantation procedures.

It should be mentioned that in 1985 an attempt at successful heart xenotransplantation from a baboon to a human (Baby Fae) failed (Bailey and others 1985). Efforts directed at prescreening the baboon for potential pathogens were deficient. Furthermore, six baboon kidneys were transplanted to patients over 30 years ago and although the kidneys were vigorously rejected, success in any form might have changed human evolution in regard to infectious agents (Starzl and others 1964). Although AIDS was not present in this country 30 years ago, African primates harbored these viruses or ones like the human form, and the potential was there to begin the first human infection. Viruses that are commonly referred to as human infections, ranging from influenza to measles, may have had a monkey virus ancestor. HTLV and SIV are two such viruses where a strong case can be made for cross-species transmission to humans. Perhaps chronic fatigue or one of the new herpesviruses discovered in humans are actually a recent accidental introduction from monkeys rather than a distant ancestral link.

A list of viruses and their potential for causing disease are given in Table 1. Selected viruses will be described below and readers are therefore referred elsewhere for more information regarding other virus types.

Retroviruses

AIDS viruses. Fortunately, the human AIDS viruses do not have a baboon homologue. However, in one study, antibodies to an African green monkey virus (SIVagm) were found in two baboons from a large seroepidemiologic survey in Tanzania (Kodama and others 1989). Recent highly sensitive polymerase chain reaction (PCR) methods were used to amplify viral DNA from peripheral lymphocytes from one of the animals, and the nucleic acid sequence matched that of a vervet SIVagm (Jin and others 1994). Other studies including our own serologic studies have failed to detect S1V infected baboons. It should be pointed out, however, that baboons might harbor a distantly related SIV that may not be detected using standard virologic and serologic assays. High background reactivity to both HIV and SIV proteins is routinely observed from African nonhuman-primate sera, including baboon sera, which does not preclude the possibility of a distantly related virus in baboons. Our studies and those of others have shown that baboon lymphocytes are resistant to infection with HIV-1 viruses (Allan unpublished data; Morrow and others 1989). On the other hand, recombinant viruses composed of the envelope from HIV-1 chimerized with SIVmac provirus easily infect baboons. Other studies have shown that baboons are susceptible to infection with HIV-2 and SIVmac and may develop AIDS-like disease (Castro and others 1991; Benveniste and others 1988). What these studies indicate is that there is no innate reason why baboons do not harbor their own SIV.

HTLV/STLV family. The first human retrovirus (HTLV) associated with disease was discovered in 1980 and in part emanated from past achievements in developing methods for growing T cells in culture. Virus could be propagated in culture and thus isolated and characterized. A disease entity recognized in Japanese populations called Adult T-cell leukemia/lymphoma was recognized in 1977 and later linked to HTLV (Cann and Chen 1990). Further studies led to the identification of a highly related monkey virus called STLV which is found in most Old World primates and its association with lymphoma has been described (Homma and others 1984; Fultz 1994; Mone and others 1992; Hubbard and others 1993). Our own studies in baboons have demonstrated that 40 percent of our colony of approximately 3,000 baboons carry STLV (Mone and others 1992). Only about 4 percent of infected animals develop lymphoma during their lifetimes, an incidence that is remarkably similar to rates seen in HTLV infected humans. Molecular analysis of baboon lymphomas showed monoclonal integration of STLV provirus indicating a role for STLV in the induction of the lymphomas (Mone and others 1992). As yet we have not identified animals with neurologic manifestations of tropical spastic paraparesis (TSP) seen in some HTLV-infected humans. STLV and HTLV-1 are genetically almost indistinguishable having over 90 percent nucleic acid sequence similarity in the env gene. HTLV can be viewed as a significant public health problem and screening of the nation's blood supply is mandatory.

Spumaviruses. Foamy viruses were first described in humans in the early 1970s and were originally linked to nasopharyngeal carcinoma, which later proved to be an erroneous association (Achong and others 1971). Seroepidemiologic surveys have found significant rates of infection in Africans while no foamy virus infection was observed in North America (Achong and Epstein 1983). On the other hand, most other animal species, including baboons, harbor species-specific foamy viruses (Neumann-Haefelin and others 1993). Unlike oncoviruses, the foamy viruses act much like immunodeficiency viruses in that they generally remain latent in many cell types including lymphocytes and when expressed, induce large multinucleated giant cells, or syncytia, and cell death, which is almost pathognomonic in SIV negative animal cultures (Flugel 1991; Allan unpublished data). Curiously, no definitive evidence as to pathogenicity of this virus has been found. The natural history of infection of foamy viruses is not well described but it would appear that these animals are infected early in life, perhaps even in utero. Obviously, generating animals that are free of foamy virus will be no small task. It must be remembered that like other retroviruses, foamy viruses must be considered capable of inducing cancers in susceptible animals. From Grave's disease to thyroiditis (Neumann-Haefelin and others 1993; Wick and others 1993), the search continues for a direct association with disease (Weiss 1988). Bone marrow induced tolerance to foamy virus infection could potentially have disastrous consequences due to the inherent pathogenicity of the virus for human cells in vitro.

Baboon endogenous viruses (BaEV). A Type C virus, recovered from placental tissue from baboons, represented the first nonhuman primate retrovirus (Benveniste and others 1974). Efforts to produce disease in experimental animals have failed, however, this virus could still represent a potential hazard in humans (Huang and others 1989). In general, retroviruses represent a serious hazard in that they integrate randomly into the host genome and under the right circumstances may induce cancers by insertional mutagenesis. A second problem that might arise is the possibility of recombinational events leading to a "new" virus. It has been estimated that as much as 0.6-1.0 % of the human genome consists of retroviral-like elements including human endogenous viruses or HERVs (Leib-Mosch and others 1992). Integration or recombination could ultimately result in the generation of mutant forms with varying degrees of pathogenicity. Just as the more lethal influenza epidemics arise by reassortment/recombination between avian and human viruses, recombinational events between baboon and human retroviruses could result in new virus types (Smith 1993; Zhang and Temin 1993). In spite of this cautionary note, there is currently no direct evidence to substantiate this possibility.

The notion that a retrovirus might induce cancer was recently realized in nonhuman primates that had been experimentally infected with murine retroviruses used in gene therapy (Vanin and others 1994). Three of ten monkeys which had received autologous bone-marrow stem cells transduced with a replication-competent MuLV, developed T-cell lymphoma. In fact, it appears that the animals had become tolerant to the viral antigens. Even though high titers of virus were recovered from the peripheral blood, no antibodies to MuLV were detected in the lymphomatous animals. In addition, a clonal pattern of MuLV integration was observed in one animal. There are several conclusions that one can draw from this study. First, retroviruses from other animal species including mice may be pathogenic in humans under the right circumstances. Second, AIDS patients treated with baboon bone-marrow stem cells may become tolerant to not only the baboon cells but also to the very pathogens contained within the baboons. While this scenario is more remote it still deserves serious consideration. Replication of baboon viruses in an immunocompromised host may additionally lead to a more rapid rate of variation and more rapid adaptation. Furthermore, retrovirus infections by themselves are generally associated with a certain incidence of cancers. Recently, studies with HIV-1 induced lymphomas have demonstrated that in addition to immunodepletion, HIV is also capable of inducing cancer through site-directed mutagenesis (Herndier and others 1992). One can also imagine that infecting an immunocompromised host with oncogenic herpesviruses, such as Herpes papio, might also accelerate leukemogenesis in that host.

Herpesviruses. There are a number of known baboon herpesviruses that are potentially hazardous in humans (Barahona and others 1974; Hilliard and others 1989). SA8 is an alphaherpesvirus that shares many properties with human herpes simplex viruses and typically causes genital and oral lesions in baboons (Botchers and Ludwig 1991). By sexual maturity, almost all baboons are infected with this agent. It is presently unknown what effect transmission of this virus would have in an immunocompromised human host. The macaque equivalent to SA8, herpes B virus, is acutely lethal in humans as mentioned previously (Kalter and Heberling 1990). The pathogenicity in humans must be considered for the baboon herpesviruses as well. Herpes papio is another herpesvirus whose human homologue is Epstein Barr virus. EBV is well-known as the primary cause of mononucleosis, or "kissing" disease, and has been linked to a variety of human cancers (Stevens 1994). Like EBV, H. papio is capable of transforming to B cells of both baboons and humans. Baboons also carry cytomegaloviruses (CMV), which are related to the human CMV strains (Hilllard and others 1989). One must consider all of these viruses as potentially harmful to humans. Efforts to eliminate these viruses from the baboon donors should be mandatory, however, there are likely to be other related herpesviruses that have not yet been identified just as new human herpesviruses are continually being discovered. The unknown consequences of infected humans with baboon herpesviruses makes this endeavor a risky proposition.

Reoviruses. Recently, an outbreak of encephalitis was observed in the baboon colony at the Southwest Foundation for Biomedical Research (SFBR). Although preliminary, it appears that the agent responsible for this disease is a previously unrecognized reovirus (Michelle Leland, personal communication, SFBR, San Antonio, Texas). It is unknown whether this virus represents a baboon reovirus or resulted from infection with a rodent or avian virus. Again, this outbreak does point out that baboons might harbor viruses that are presently uncharacterized but may represent a significant public health hazard to humans.

Picornaviruses. Although baboons carry several picomaviruses, including coxsackie viruses (Kalter and Heberling 1990), a recent epidemic in baboons of the SFBR baboon colony was associated with high mortality. More than 80 animals died of acute myocarditis while many more animals became infected and survived. An encephalomyocarditis virus (EMCV) was identified and was apparently contracted from resident rodent populations (Hubbard and others 1992). The severity of the outbreak has not been fully investigated but several hundred animals became clinically ill during one 9-month period. The fact that baboons were infected with a rodent virus that was acutely lethal points out that it is imperative that baboons used for organ donation are raised from infancy to adulthood in an environment free from the possibility of contracting a virus from either rodents or birds. Most of the baboons at the SFBR are reared in conditions that expose them to the outside environment, which is also a source of enrichment. However, contact with other species can occur leading to avian-primate or rodent-primate transmissions.

Spongiform encephalopathies. Although not strictly members of the virus family, a group of maladies with a common thread are the slowly progressive encephalopathies, each manifested by an abnormal accumulation of amyloid deposits in the brain (Chesebro 1990). While a baboon scrapie-like agent has yet to be described, it is not unreasonable to imagine a similar vires-like entity found naturally in baboons. Since scrapie was first described in sheep (Sigurdsson 1954), a number of similar syndromes have been elucidated with the more famous study related to Kuru, a disease linked to cannibalism in New Guinea. Gajdusek found that humans that had consumed brains and other tissues from deceased relatives developed a debilitating neurodegenerative disease with pathologic findings remarkably similar to scrapie in sheep (Gajdusek and Zigas 1957). Indeed, the infection and disease could be transmitted experimentally to chimps (Gajdusek and others 1967). Other scrapie-like disease entities have also been reported in humans and include Creutzfeldt-Jakob Disease (CJD) and Gerstmann-Straussler Syndrome (Duffy and others 1974; Masters and others 1981). Most recently, "Mad Cow" disease or bovine spongiform encephalopathy arose by feeding cows bone meal from sheep (Wells and others 1987). A similar disease has not been observed in baboons, but a detailed study has not been undertaken. In the event that a scrapie-like agent was present in baboon tissue and transmitted to humans, it is unlikely to be transmitted to others since its route of transmission is primarily through cannibalism or transplantation.

ANDROMEDA STRAIN REVISITED

While Michael Crichton's best-selling science fiction novel is firmly implanted into the public's awareness, the relative risk of an acutely lethal and highly contagious viral disease is mostly improbable. Consider that humans have been in contact with most other nonhuman primates whether in zoos or in the wild for hundreds if not thousands of years, and any catastrophic viral disease emanating from easily transmitted viruses would have materialized by now. Viruses transmitted by fecal-oral or respiratory routes have probably been transmitted from monkey to human over the years and it is possible that some of the viral strains circulating in human populations today might have had their origins in monkeys. The more serious known zoonotic infections from monkeys to humans have already been mentioned. Many bacterial pathogens are readily transmitted among primates such as Shigella, and tuberculosis is a serious concem at primate centers, since macaques are highly susceptible to infection accompanied by advanced disease (Michaels and Simmons 1994). A new emerging viral disease resulting from xenogeneic transplantation could take many forms with as many outcomes as the mind can imagine. The most insidious threats are those viral infections that are largely silent ones which might only become fulminant at some later time and perhaps only in a small percentage of the infected population.

By understanding the intricacies of how AIDS is spread, and the pathogenesis of other more slowly progressive diseases such as the spongiform encephalopathies, multiple sclerosis, or Alzheimer's disease, one can easily weave together possible candidate diseases. It should be remembered that our public health agencies are most successful at investigating infections that have acute morbidity and mortality. On the other hand, our success at stemming the tide of persistent slow virus infections is abysmal. From AIDS to hepatitis, we are still struggling to find cures and vaccines to safeguard the uninfected population. Despite our best efforts, the percentage of people infected with HIV continues to rise due to our inability to moderate human behavior and the persistency of the infection. The fact that the virus tags along with human sexual activity really hinders our efforts at control. It is therefore easy to imagine that the more difficult viruses to detect and eliminate will be sexually transmitted or blood borne, similar to AIDS.

Another level of complexity is apparent when one considers the risk associated with bone marrow transplants from baboons. Given that the baboon bone-marrow cells harbor several virus infections with proven pathogenicity for human cells in vitro, a healthy baboon immune system would maintain a full repertoire of anti-viral responses that would limit virus replication in the human recipient. Should the baboon bone marrow also function in limiting progression to AIDS and should the recipient recover, that individual might become a cauldron for silent epidemics, a modem day Typhoid Mary. Even though his or her chimerized immune system may keep those monkey viruses in check, transmission through intimate contact to sexual partners could then lead to demonstrable illness since the partner's immune system has likely never seen the baboon viruses. Efforts to pinpoint the origins of these new diseases would also be more difficult since the cases are once removed from the transplant recipients.

FUTURE CONSIDERATIONS AND RECOMMENDATIONS

Transplant specialists are determined to proceed with studies directed toward xenogeneic transplantation. Over 30 years have gone into its development and these baboon xenogeneic studies are a culmination of those efforts. I cannot separate the good of saving a human life through transplantation from the risk of introducing a pathogen that will likely change human evolution in some profound way. I view xenograft tissues as essentially very complex vectors for shuttling new viruses into humans. All major natural barriers to viral infections that have evolved during the millennia will have been circumvented by a single surgical procedure. It is time to stop and weigh the evidence against and in favor of transplantation. Once the pendulum is set in motion, baboon viruses will certainly become established in the human population. The only real questions will then be, how serious will be the consequences of such actions? How serious will the inevitable disease (or diseases) be? How will they manifest themselves? Obviously we can't predict the outcome.

There are a few recommendations that might aid in reducing the overall risk to humans from these types of procedures, if it is decided that xenogeneic transplantations are to continue. Selected recommendations are as follows:

· Form an independent panel of scientists and surgeons to address the issues discussed above. This panel may be chartered either through the Institute of Medicine or through the auspices of the National Institutes of Health and the Centers for Disease Control and Prevention. Their charge should be to thoroughly weigh the facts and relative risk that these operations are likely to create, which should include ethical considerations.

· Initiate studies that address the virologic repertoire in baboons. Is this the best nonhuman primate species to use for such studies based on its viral flora? Thorough examination of virus types through state-of-the-art viral detection and isolation methodologies should be instituted. Most of the viruses harbored by baboons have been only marginally characterized. For example, is there a significant population of baboons that carries STLV without detectable antibody responses? How are foamy viruses transmitted and at what age?

· Scrutinize currently available tests for the known viral pathogens. Are diagnostic tests adequate for screening animals for a multitude of viral etiologies? A negative test result should not be misconstrued as anything other than negative as far as that test is concerned. This finding in no way determines actual virus status, and is only predictive of virus burden. Most of the assays used to screen for viral infections in baboons were developed for use in humans. For example, most African green monkeys would not be considered SIVagm positive by immunoblotting methods if the criteria used for humans infected with HIV-1 were used in monkeys.

· Develop tests for viruses that we know are carried by baboons but for which we have no reliable assays. One important example of this problem is the lack of reliable testing for foamy viruses. Serologic tests may discriminate among the various foamy virus types but the sensitivity of these types of assays are suspect. Most of the assays specific for nonhuman primates have not been put under the same microscope as those used for human testing. It is time to develop more stringent criteria and testing methods to screen potential animal donors. In some cases, direct virus isolation techniques should follow an antibody based assays so as to decrease the possibility of a virus positive, and antibody negative animal.

· Provide specific pathogen-free (SPF) colony-bred animals. It's not enough to limit the use of baboons to colony raised animals in place of wild caught animals. SPF baboon colonies can be developed but would be expensive and would create a long lag time until the first baboon could be furnished as a donor. SPF colonies have been established for rhesus monkeys for use in AIDS vaccine testing; these monkeys are free of SIV, STLV, Herpes B virus and Type D retroviruses (Lerche and others 1994; Ward and Hilliard 1994). Very stringent screening methods followed by housing constraints require at least three years before the first group of animals become available. It should be emphasized that SPF only denotes that the animal is free of specific pathogens and not free of all pathogens. One can easily be lulled into thinking that somehow these animals are safe for transplantation when in fact they still harbor any number of viruses (those viruses not part of the SPF list of agents). Because some viruses may be transmitted early in life, cesarean section delivery and removal of the newborns to a sterile environment where they can be reared away from viral flora circulating in the baboon colony, might aid in reducing their virus burden. In addition, animals prescreened and selected as donors can be extensively treated with gancyclovir or acyclovir along with zidovidine to reduce the expression of herpesviruses and retroviruses respectively. Yet, even with these measures, baboon viruses will surely take up residence in human recipients.

Despite all of the best efforts to provide a "clean" baboon for donating organs or cells to humans, the best strategy for preventing xenotransmission is still not to do them. in this brief article, I have provided several examples of primate viruses that have escaped into the human population. Are we to surmise that we have found all there is in these monkeys? I think not. It's time to think about what we can learn from these diseases before we jeopardize the human race. Trying to cure a disease (AIDS) that presumably emerged by close human contact with monkeys by implanting monkey tissue into AIDS patients makes very little sense when viewed from a public health perspective.

ACKNOWLEDGMENTS

I wish to thank Julia Hilliard for helpful discussions and critical review and Michelle Leland for providing unpublished data concerning the epidemiology of baboon reovirus-like viral encephalitis.

REFERENCES

Achong, B. G., P. W. A. Mansell, M. A. Epstein, and P. Clifford. 1971. An unusual virus in cultures from a human nasopharyngeal carcinoma. J. Natl. Cancer Inst. 46:299-302.

Achong, B. G., and M. A. Epstein. 1983. Naturally occurring antibodies to the human syncytial virus in West Africa. J. Med. Virol. 11:53-57.

Allan, J. S. 1992. Viral evolution and AIDS. J. NIH Res. 4:51-54.

Allan, J. S. 1994. Primates and New Viruses. Science (Letter) 265:1345-1346.

Allan, J. S., M. S. Short, M. E. Taylor, S. Su, V. M. Hirsch, P. R. Johnson, G. M. Shaw, and B. H. Hahn. 1991. Species-specific diversity among simian immunodeficiency viruses from African green monkeys. J. Virol. 65:2816-2828.

Bailey, L. L., S. L. Nehlsen-Cannarella, W. Concepcion and W. B. Jolley. 1985. Baboon-to-human cardiac xenotransplantation in a neonate. J. Am. Med. Assoc. 254:3321-3329.

Barahona, H., L. V. Melendez, and J. L. Melnick. 1974. A compendium of herpesviruses isolated from non-human primates. Intervirology 3:175-192.

Barin, F., S. M. Boup, F. Denis, P. J. Kanki, J. S. Allan, T. H. Lee, and M. Essex. 1985. Serological evidence for a virus related to simian T-lymphotropic retrovirus III in residents of West Africa. Lancet I1:1387-1389.

Benveniste, R. E., M. M. Lieber, D. N. Livingston, C. L. Sherr, G. J. Todaro, and S. S. Kalter. 1974. Infectious C-type virus isolated from a baboon placenta. Nature 248:17-20.

Benveniste, R. E., W. R. Morton, E. A. Clark, C. C. Tsai, H. D. Ochs, J. M. Ward, L. Kuller, W. B. Knott, R. W. Hill, M. J. Gale, and M. E. Thouless. 1988. Inoculation of baboons and macaques with simian immunodeficiency virus/Mne, a primate lentivirus closely related to human immunodeficiency virus type 2. J. Virol. 62:2091-2101.

Borchers, K., and H. Ludwig. 1991. Simian agent 8--a herpes simplex-like monkey virus. Comp. Immun. Microbiol. Infect. Dis. 14:125-132.

Cann, A. J., and I. S. Y. Chert. 1990. Human T-cell leukemia virus types I and Il. Pp. 1501-1527 in Fields Virology, Vol. 2, 2d Edition, B. N. Fields and D. M. Knipe, eds. New York: Raven Press.

Carbone, M., H. I. Pass, P. Rizzo, M. Marinetti, M. Di Muzio, D. Mew, A. S. Levine, and A. Procopio. 1994. Simian virus 40-like DNA sequences in human pleural mesothelioma. Oncogene 9:1781-1790.

Castro, B. A., M. Nepomuceno, N. W. Lerche, J. E. Eichberg, and J. A. Levy. 1991. Persistent infection of baboons and rhesus monkeys with different strains of HIV-2. Virology 184:219-226.

Chesebro, B. 1990. Spongiform encephalopathies: The transmissible agents. Pp. 2325-2336 in Fields Virology, Vol. 2, 2d Edition, B. N. Fields and D. M. Knipe, eds. New York: Raven Press.

Clavel, F., D. Guetard, F. Brun-Vezinet, S. Chamaret, M. A. Rey, M. O. Santos-Ferreira, A. Laurent, C. Dauguet, C. Karlama, C. Rouzioux, D. Klatzmann, J. L. Champalimaud, and L. Montagnier. 1986. Isolation of a new human retrovirus from West African patients with AIDS. Science 233:343-346.

Curtis, T. 1992. The origins of AIDS. Rolling Stone. March 19.54-107.

Dalgard, D. W., R. J. Hardy, S. L. Pearson, G. J. Pucak, R. V. Quander, P. M. Zack, C. J. Peters, and P. B. Jahrling. 1992. Combined simian hemorrhagic fever and Ebola virus infection in cynomolgus monkeys. Lab. Anim. Sci. 42:152-157.

Dalgleish, A. G., P. C. Beverly, P. R. Clapham, D. H. Crawford, M. F. Greaves, and R. A. Weiss. 1985. The CD4 (T4) antigen is an essential component of the receptor for AIDS retrovirus. Nature (London) 312:763-767.

Daniel, M. D., N. L. Letvin, N. W. King, M. Kannagi, P. K. Sehgal, R. D. Hunt, P. J. Kanki, M. Essex, and R. C. Desrosiers. 1985. Isolation of a T-cell tropic HTLV-III-Iike retrovirus from macaques. Science 228:1201-1204.

Duffy, P., J. Wolf, G. Collins, A. G. DeVoe, B. Streetem and B. Cowen. 1974. Possible person-to-person transmission of Creutzfeldt-Jakob disease. New Engl. J. Med. 290:692-693.

Essex, M. 1994. Simian immunodeficiency virus in people. New Engl. J. Med. 330:209-210.

Fenner, F. 1993. Human monkey pox: A newly discovered human virus disease. Pp. 176-183 in Emerging Viruses, S. S. Morse, ed. New York: Oxford University Press.

Flugel, R. M. 1991. Spumaviruses: A group of complex retroviruses. J. AIDS 4:739-750.

Fultz, P. N., H. M. McClure, D. C. Anderson, R. B. Swenson, R. Anand, and A. Srinivasan. 1986. Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabeys (Cercocebus atys). Proc. Natl. Acad. Sci. USA 83:5286-5290.

Fultz, P. N. 1994. Simian T-lymphotropic virus type I. Pp. 111-131 in The Retroviridae, Vol. 3 of The Viruses Series, J. A. Levy, ed. New York: Plenum Press.

Gajdusek, D. C., and V. Zigas. 1957. Degenerative disease of the central nervous system in New Guinea: The endemic occurrence of kuru in the native population. N. Eng. J. Med. 257:974-978.

Gajdusek, D. C., C. J. Gibbs, and M. Alpers. 1967. Transmission and passage of experimental Kuru to chimpanzees. Science 155:212-214.

Herndier, B. G., B. T. Shiramizu, N. E. Jewett, K. D. Aidape, G. R. Reyes, and M. S. McGrath. 1992. Acquired immunodeficiency syndrome-associated T-cell lymphoma: Evidence for human immunodeficiency virus type 1-associated T-cell transformation. Blood 79:1768-1774.

Hilliard, J. K., D. Black, and R. Eberle. 1989. Simian alphaherpesviruses and their relation to the human herpes simplex viruses. Arch Virol 109:83-102.

Hirsch, V. M., R. A. Olmsted, M. Murphey-Corb, R. H. Purcell, and P. R. Johnson. 1989. An African primate lentivirus (SIVsm) closely related to HIV-2. Nature(London) 339:389-392.

Hjelle, B., S. Jenison, N. Torrez-Martinez, T. Yamada, K. Nolte, R. Zumwalt, K. Macinnes, and G. Myers. 1994. A novel hantavirus associated with an outbreak of fatal respiratory disease in the southwestern United States: Evolutionary relationships to known hantaviruses. J. Virol. 68:592-596.

Hollinger, F. B. 1990. Hepatitis B virus. Pp. 2171-2236 in Fields Virology, Vol. 2, 2d Edition, B. N. Fields and D. M. Knipe, eds. New York: Raven Press.

Holmes, G. P., J. K. Hilliard, K. C. Klontz, A. H. Rupert, C. M. Schindler, E. Parrish, G. Griffin, G. S. Ward, N. D. Bernstein, T. W. Bean, M. R. Ball, J. A. Brady, M. A. Wilder, and J. E. Kaplan. 1990. B virus (herpes simiae) infection in humans: Epidemiologic investigation of a cluster. Ann. Int. Med. 112:833-839.

Homma, T., P. J. Kanki, N. W. King, R. D. Hunt, M. J. O'Connell, N. L. Letvim M. D. Daniel, R. C. Desrosiers, C. S. Yang, and M. Essex. 1984. Lymphoma in macaques: association with virus of human T lymphotropic family. Science 225:716-718.

Houff, S. A., R. C. Burton, R. W. Wilson, T. E. Henson, W. T. London, G.M. Baer, L. J. Anderson, W. G. Winkler, D. L. Madden, and J. L. Sever. 1979. Human-to-human transmission of rabies virus by comeal transplant. New. Engl. J. Med. 300:603-604.

Huang, L. H., J. Silberman, H. Rothschild, and J. G. Cohen. 1989. Replication of baboon endogenous virus in human cells. J. Biol. Chem. 264:8811-8814.

Hubbard, G. B., K. F. Soike, T. M. Butler, K. D. Carey, H. Davis, W. I. Butcher, and C. J. Ganntt. 1992. An encephalomyocarditis virus epizootic in a baboon colony. Lab. Anim. Sci. 42:233-239.

Hubbard, G. B., J. P. Mone, J. S. Allan, K. J. Davis, M. M. Leiand, P. M. Banks, and B. Smir. 1993. Spontaneously generated non-Hodgkin's lymphoma in twenty-seven simian T-cell leukemia virus type I antibody-positive baboons (Papio species). Lab. Anim. Sci. 43:301-309.

Ildstad, S. T., M. S. Vacchio, P. M. Markus, M. L. Hronakes, S. M. Wren, and R. J. Hodes. 1992. Cross-species transplantation tolerance: Rat bone marrow-derived cells can contribute to the ligand for negative selection of mouse T cell receptor vB in chimeras tolerant to xenogeneic antigens. J. Exp. Med. 175:147-155.

Ion-Nedelcu, N., A. Dobrescu, P. M. Strebel, and R. W. Sutter. 1994. Is southwest U.S. mystery disease caused by hantavirus? Lancet 343:53-54.

Jahrling, P. B., T. W. Gelsbert, D. W. Dalgard, E. D. Johnson, T. G. Ksiazek, W. C. Hall, and C. J. Peters. 1990. Preliminary report: Isolation of Ebola virus from monkeys imported to USA. Lancet 335:502-505.

Jin, M. J., J. Rogers, J. E. Phillips-Conroy, J. S. Allan, R. C. Desrosiers, G. M. Shaw, P. M. Sharp, and B. H. Hahn. 1994. Infection of a yellow baboon with simian immunodeficiency virus from African green monkeys: Evidence for cross-species transmission in the wild. J. Virol. 68:8454-8460.

Kalter, S. S., and R. L. Heberling. 1990. Primate viral diseases in perspective. J. Med. Primaroi. 19:519-535.

Kanki, P. J., R. Kurth, W. Becket, G. R. Dreesman, M. F. McLane, and M. Essex. 1985a. Antibodies to simian T-lymphotropic retrovirus type III in African green monkeys and recognition of STLV-III viral proteins by AIDS and related sera. Lancet i:1330-1332.

Kanki, P. J., M. F. McLane, N. W. King, N. L. Letvin, R. D. Hunt, P. K. Sehgal, M. D. Daniel, R C. Desrosiers, and M. Essex. 1985b. Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to HTLV-III. Science 228:1199-1201.

Khabbaz, R. F., W. Heneine, J. R. George, B. Parekh, T. Towe, T. Woods, W. M. Switzer, H. M. McClure, M. Murphey-Corb, and T. M. Folks. 1994. Brief Report: Infection of a laboratory worker with simian immunodeficiency virus. New. Engl. J. Med. 330:172-177.

Kissling, R. E, R. Q. Robinson, F. A. Murphy, and S. G. Whitfield. 1968. Agent of disease contracted from green monkeys. Science 160:888-890.

Kodama, T., D. P. Silva, M. D. Daniel, J. E. Phillips-Conroy, C. J. Jolly, J. Rogers, and R. C. Desrosiers. 1989. Prevalence of antibodies to SIV in baboons in their native habitat. AIDS Res. Hum. Retroviruses 5:337-343.

Koprowski, H. 1992. AIDS and the polio vaccine. Science 257:1024-1025.

Lecatsas, G., F. A. Neethling, W. A. De Klerk, and B. Gridelli. 1992. Filovirus seropositivity in prospective organ donor baboons. Transplant. Proc. 24:617-618.

Leib-Mosch, C., M. Bachmann, R. Brack-Wemer, T. Wemer, V. Erfle, and R. Hehlmann. 1992. Expression and biological significance of human endogenous retroviral sequences. Leukemia 6:72S-75S.

Lerche, N. W., J. L. Yee, and M. B. Jennings. 1994. Establishing specific retrovirus-free breeding colonies of macaques: An approach to primary screening and surveillance. Lab. Anim. Sci. 44:217-221.

Letvin, N. L., M. D. Daniel, P. K. Sehgal, R. C. Desrosiers, R. D. Hunt, L.M. Waldron, J. J. MacKey, D. K. Schmidt, L. V. Chalifoux, and N. W. King. 1985. Induction of AIDS-like disease in macaque monkeys with T-cell lymphotropic retrovirus STLV-III. Science 230:71-73.

Marlink, R., P. Kanki, I. Thior, K. Travers, G. Eisen, T. Siby, I. Traore, C.-C. Hsieh, M. C. Dia, E.-H. Gueye, J. Hellinger, A. Gueye-Ndiaye, J.-L. Sankale, I. Ndoye, S. Mboup, and M. Essex. 1994. Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science 265:1587-1590.

Masters, C. L., D. C. Gajdusek, and C. J. Gibbs. 1981. Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Straussler syndrome. Brain 104:559-588.

Michaels, M. G., and R. L. Simmons. 1994. Xenotransplant-associated zoonoses. Transplantation 57:1-7.

Monath, T. P. 1994. Yellow fever and dengue--the interactions of virus, vector and host in the re-emergence of epidemic disease. Sem. Virol. 5:133-145.

Mone, J. P., E. W. Whitehead, M. M. Leiand, G. B. Hubbard, and J. S. Allan. 1992. Simian T-cell leukemia virus type I infection in captive baboons. AIDS Res. Hum. Retrovir. 8:1653-1661.

Morrow, J. W., J. Homsy, J. W. Eichberg, J. Krowka, L.-Z. Pan, I. Gaston, H. Legg, N. Lerche, J. Thomas, and J. A. Levy. 1989. Long-term observation of baboons, rhesus monkeys, and chimpanzees inoculated with HIV and given periodic immunosuppressive treatment. AIDS Res. Hum. Retrovir. 5:233-245.

Morse, S. S., and A. Schluederberg. 1990. Emerging viruses: The evolution of viruses and viral diseases. J. Inf. Dis. 162:1-7.

Morse, S.S. 1994. The viruses of the future? Emerging viruses and evolution. Pp. 325-335 in The Evolutionary Biology of Viruses, S. Morse, ed. New York: Raven Press.

Mortimer, E. A., M. L. Lepow, E. Gold, F. C. Robbins, G. J. Burton, and J. F. Traumeni. 1981. Long-term follow-up of persons inadvertently inoculated with SV40 as neonates. New. Engl. J. Med. 305:1517-1518.

Murphey-Corb, M., L. N. Martin, S. R. Rangan, G. Baskin, B. J. Gormus, R. H. Wolf, W. A. Andes, M. West, and R. C. Montelaro. 1986. Isolation of an HTLV-III-related retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys. Nature(London) 321:435-437.

Murphy, F. A., and N. Nathanson. 1994. The emergence of new virus diseases: An overview. Semin. Virol. 5:87-102.

Murphy, F. A. 1994. New, emerging, and reemerging infectious diseases. Adv. Virus Res. 43:1-52.

Myers, G., K. Macinnes, and B. Korber. 1992. The emergence of simian/ human immunodeficiency viruses. AIDS Res. Hum. Retrovir. 8:373-386.

Neumann-Haefelin, D., U. Fieps, R. Renne, and M. Schweizer. 1993. Foamy Viruses. lntervirol. 35:196-207.

Peeters, M., K. Fransen, E. Delaporte, M. Van den Haesevelde, G.-M. Gershy-Damet, L. Kestens, G. van den Groen, and P. Piot. 1992. Isolation and characterization of a new chimpanzee lentivirus (simian immunodeficiency virus isolate cpz-ant) from a wild-captured chimpanzee. AIDS 6:447-451.

Peterman, T. A., K.-J. Lui, D. N. Lawrence, and J. R. Allen. 1987. Estimating the risks of transfusion-associated acquired immune deficiency syndrome and human immunodeficiency virus infection. Transfusion 27:371-4.

Peters, C. J., A. Sanchez, H. Feldmann, P. E. Rollin, S. Nichol, and T. G. Ksiazek. 1994. Filoviruses as emerging pathogens. Sem. Virol. 5:147-154.

Ricordi, C., A. G. Tzakis, W. B. Rybka, P. Fontes, E. D. Ball, M. Trucco, M. Kocova, D. Triulzi, J. McMichael, H. Doyle, P. Gupta, J. J. Fung, and T. E. Starzl. 1994. Xenotransplantation of hematopoietic cells resistant to H1V as a potential treatment for patients with AIDS. Transplant. Proc. 26:1302-1303.

Shah, K., and N. Nathanson. 1976. Human exposure to SV40: Review and comment. J. Epidemiol. 103:1-11.

Sigurdsson, B. 1954. Rida, a chronic encephalitis of sheep: With general remarks on infections which develop slowly and some of their special characteristics. Br. Vet. J. 110:341-354.

Smith, D.M. 1993. Endogenous retroviruses in xenografis. Lancet 328:142-143.

Starzl, T. E., T. L. Marchioro, G. N. Peters, C. H. Kirkpatrick, W. E. C. Wilson, K. A. Porter, D. Rifkind, D. A. Ogden, C. R. Hitchcock, and W. R. Waddell. 1964. Renal heterotransplantation from baboon to man: Experience with 6 cases. Transplantation 2:752-776.

Starzl, T. E., A. Tzakis, J. J. Fung, S. Todo, A. J. Demetris, R. Manez, I. R. Marino, L. Valdivia, and N. Murase. 1994. Prospects of clinical xenotransplantation. Transplant. Proc. 26:1082-1088.

Stevens, J.G. 1994. Overview of herpesvirus latency. Sem. Virol. 5:191-196.

Vanin, E. F., M. Kaloss, C. Broscius, and A. W. Nienhuis. 1994. Characterization of replication-competent retroviruses from nonhuman primates with virus-induced T-cell lymphomas and observations regarding the mechanism of oncogenesis. J. Virol. 68:4241-4250.

Ward, J. A., and J. K. Hilllard. 1994. B virus-specific pathogen-flee (SPF) breeding colonies of macaques: Issues, surveillance, and results in 1992. Lab. Anim. Sci. 44:222-228.

Weigler, B.T. 1992. Biology of B virus in macaque and human hosts: A review. Clin. Inf. Dis. 14:555-567.

Weiss, R. A. 1988. Foamy retroviruses. A virus in search of a disease. Nature 333:497-498.

Wells, G. A. H., A. C. Scott, C. T. Johnson, R. F. Gunning, R. D. Hancock, M. Jeffrey, M. Dawson, and R. Bradley. 1987. A novel progressive spongiform encephalopathy in cattle. Vet. Record 121:419-420.

Wick, G., T. Klemens, A. Aguzzi, H. Recheis, H. Andeft, and B. Grubeck-Loebenstein. 1993. Possible role of human foamy virus in Grave's disease, lntervirol. 35:101-107.

World Health Organization (WHO). 1978. Ebola haemorrhagic fever in Zaire. Bull. WHO 56:271-293.

Zhang, J., and H. Temin. 1993. Rate and mechanism of nonhomologous recombination during a single cycle of retroviral replication. Science 259:234-238.

TABLE 1 Viruses of significance to baboon--human transplantation

Virus	Examples of Pathogenicity
Retroviruses Human and Simian Immunodeficiency Viruses HIV-1 SIVagm HIV-2 SIVmac SHIV SIVbab? STLV/HTLV BaEV-baboon endogenous virus	AIDS in humans and Asian macaques Leukemia/Lymphoma Unknown-cancer
Spumaviruses (Foamy) Other-Type D, other endogenous	Unknown-cancer, Graves diseases, other Unknown-cancer
Herpesviruses SA8 H.Papio CMV	Genital lesions, abortions Cancer? Immunosuppression, cancer?
Papoviruses SA12	Unknown-cancer?
Picornaviruses EMCV	Acutely fatal myocarditis
Spongiform encephalopathies	Kuru, Creutzfeldt Jakob disease, scrapie agent
Uncharacterized reovirus	Encephalitis
Other Rabies monkeypox	Rapidly fatal neurologic Like smallpox, fatal in 10% of human cases