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Endogenous retroviruses, are unlike viruses like West Nile in that they do not cause disease in their animal hosts. They are the remnants of viral infections that long ago infected the species and long ago retired into dormancy. The hypothesis is that they are remnants of past epidemics where the viruses moved into the entire species, actually becoming part of the germ cell line. For instance, gibbon ape leukemia virus, a retrovirus endogenous to that species, was most likely introduced into the gibbon ape from Asian mouse populations. All mammalian species have these endogenous retroviruses.

"It is estimated that from three to eight percent of our genome is endogenous retroviral sequence," says Salomon. "It is not functional, but our genome is filled with these sequences."

Many of these are defective, but some of them can code for a complete and infectious viral particle. The fear with xenotransplantation is that the viral genes may come out of retirement.

"A group of us said, 'Wait a minute, what about the potential of [PERV] infections being introduced into humans by xenotransplantation and then spreading to the public at large?'" says Salomon. "We were not very popular at the time."

Around the same time, in 1997, Robin Weiss and his colleagues at Oxford reported to Nature that porcine endogenous retroviruses could infect human cells in vitro. That result sparked a great deal of debate and led some to call for a moratorium on xenotransplantation.

Salomon rejected those calls and instead advocated for proceeding with clinical trials, but cautiously and in carefully defined, highly controlled, and well monitored trials. And if there is any evidence of real and productive infection, he adds, then everything should be closed down. Xenotransplantation is a new field and with any new technology there are potential risks. If we close down new directions in medicine every time there is a theoretical risk identified than there will be little progress made.

"The bottom line is this: we need to advance our understanding of PERV to make an informed prediction of risk to the human patient and human population," he says. "[And] we need to assess the risk based on good science and not on dramatics."

A Hierarchy of Questions

Weiss's 1997 study demonstrated that a risk exists, but did not determine how much of a risk it is.

Would a pig cell transplanted into a human make a virus? If it made a virus, would the virus be transmitted to the human cells? If the transmission occurred, would the virus become productive or would it stay dormant? If the virus were productive, would it spread to other cells and organs? If the virus spread, would it cause disease in the person? If it caused disease, would it also be transmissible? If so, how? What would be the consequences to public health?

And even if one were able to answer all these questions, determining how to shape policy based on them may not be so straightforward. If, for instance, a person's xenotransplant will cause disease, he/she can still make an informed consent to receive it. After all, having the transplant and living with the risk of disease is better than not having it and dying with no disease. However, if there is also a risk that the transplant recipient could infect others, then the solution is not so straightforward. One cannot consent to placing someone else at risk.

"It is the transition from individual risk to public health risk where the real controversy comes," says Salomon.

Salomon has spent the last several years trying to work out some of the science-based answers to this hierarchy of risk questions.

Productive Infection

Two years ago Salomon and his colleagues demonstrated that pig islets make infectious virus and infect mouse and human cells that have been implanted into in vivo models. In other words, when scientists transplanted pig islets under conditions similar to what might be seen in the clinic, they saw PERV replicate and infect other cells.

"You have to face the fact that there is virus coming out of that transplanted pig tissue and that [the virus] is replication competent and infectious," he says.

He recently cloned, with investigator Clive Patience at Immerge Biotherapeutics and investigator Robin Weiss and his colleagues at Oxford, two previously unknown genes that encode human receptors of PERV. They are in the process of transfecting the receptors into the germline of mice and demonstrating whether they are able to get productive infection.

"If it works, we will have a new model," he says. This will allow them to study the pathology of PERV in living tissue—since in pigs, the viruses cause no disease.

Even before they finish these models they have already demonstrated that the human receptor works well when transfected into mouse cells. They are currently defining the functionality of the receptors, expression in different human tissues and studying their binding mechanisms in order to ascertain what is happening.

This is all simply establishing whether the possibility exists for productive infection, which is an important issue because the family of retroviruses to which PERV belongs are all leukemia viruses—diseases that cause hematological malignancies.

"We're still working our way through the hierarchy," cautions Salomon. "We haven't talked about disease yet and we haven't talked about potential public health risks. But our understanding of how PERV enters cells and produces productive infection has increased significantly."


But patients are not waiting for these answers. Shortly before agreeing to an interview, Salomon had established contact with a doctor in Mexico who has already transplanted pig islets obtained from a company in New Zealand into 12 adolescents and is planning to expand his trials to include 24 more.

Would people go to Mexico or some other country for the transplant and then return to the United States or elsewhere the procedure is not yet approved?

There is already a booming black market in organ transplants, which Salomon has witnessed first-hand in the clinic. Unlike transplant tourism, though, what Salomon has called "xenotourism" is a far greater concern because of the unanswered questions about possible dangers of disease and infection caused by PERV and other animal pathogens that might be introduced into humans especially in uncontrolled trials."

"It is in no way exaggerated to raise the concern," Salomon says. In fact, he is now working with the staff of the U.S. Secretary of Health to formulate a plan to disseminate basic information on the potential danger of xenotourism and, hopefully, discourage U.S. citizens from participating in such foreign adventures.



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A confocal micrograph (630X) of SIRC cells expressing a C-terminal EGFP-tagged PERV receptor. Expression of this engineered fluorescent receptor is one tool being used in experiments to study the cellular distribution of receptor before and after exposure to infectious virus.