PERV Receptors Found in Humans

By Jason Socrates Bardi

Otto von Bismarck notwithstanding, public health decisions are best made when they are based on the soundest scientific evidence, and the ideal public health debate simply sorts and presents that evidence. In the real world, public health debates are not always so ideal. Case in point is the debate over xenotransplantation, the transplantation of organs and tissues from animals into humans, where scientific risk assessment has not always been so easy.

However, a recent study, appearing in an upcoming issue of Proceedings of the National Academy of Sciences, opens up avenues of research necessary for a more complete and objective assessment of the risks of pig to human xenotransplantation. The research team was led by Clive Patience of Immerge BioTherapeutics, Inc. and includes Daniel R. Salomon, associate professor in The Scripps Research Institute (TSRI) Department of Molecular and Experimental Medicine.

At issue is the risk versus the reward to society of procedures using animal tissues in humans.

The rewards are easy to envision. Take Type 1 diabetes, for instance. Less than a hundred years ago, a diagnosis of Type 1 diabetes was almost a death sentence, and patients were not considered likely to live more than a few years at the most. The discovery of insulin in the 1920s changed that dramatically, so long as patients continued to inject the drug daily. In the last few decades, the human pancreatic transplant has given many patients with Type 1 diabetes healthy, insulin-producing organs and the ability to move off injections. And the experimental procedure of transplanting "islet" cells from pancreata promises to be an even faster and less invasive way of achieving the same result.

However, while the disease afflicts about 1.5 to 1.8 million Americans and accounts for 30,000 newly diagnosed cases each year, only about 5,000 whole human pancreata are available for transplantation in a given year. The case for xenotransplantation, then, is simple. If pancreata and pancreatic islets could be recovered from another source, say from pigs, many more patients could be treated for major health problems.

The potential risks, on the other hand, are also sizable. Xenotransplantation might lead to the transmission of porcine microorganisms, particularly porcine endogenous retrovirus (PERV), one of the dormant endogenous retroviruses that are common to mammals. PERV was first shown to infect human cells in vitro by Clive Patience, Takayuki Miyazawa, and Robin A. Weiss, who published their results in Nature Medicine in 1998. Dr. Salomon and his group followed with a publication in Nature (2000) demonstrating that when pig islets were transplanted into immunodeficient mice PERV was transmitted in vivo to mouse cells. However, no evidence of continued viral replication or disease was found.

However, the actual risk of infection with PERV for patients receiving xenotransplants has remained unclear. Even less clear has been whether there is risk of subsequent transmission of PERV to other humans and if so how much risk. This lack of information makes intelligent debate and decision making difficult. In order to assess this risk and move the debate forward, a number of scientists around the world have worked for the last several years to understand and define these benefits and risks through carefully defined, highly controlled, and well monitored research.

In the recent Proceedings of the National Academy of Sciences study, the research group identified two sequence-related human proteins that act as receptors for a porcine endogenous retrovirus known as PERV-A. They also describe homologs from baboon and porcine cells that also are active as receptors. Sequence analysis indicates that these receptors are multiple membrane-spanning proteins similar to receptors for other gammaretroviruses and that expression is widespread in human tissues including peripheral blood mononuclear cells, but their biological functions are unknown.

This identification of the PERV-A receptors opens the way for further research necessary for a quantitative assessment of the risks associated with pig to human xenotransplantation because it provides a way of creating human receptor-transgenic animals as new models for the PERV infection and a way of making a series of receptor construction chimeras to define host cell and pathogen interactions at a molecular level.

To read the article, "Identification of receptors for pig endogenous retrovirus" by Thomas A. Ericsson, Yasuhiro Takeuchi, Christian Templin, Gary Quinn, Shelli F. Farhadian, James C. Wood, Beth A. Oldmixon, Kristen M. Suling, Jennifer K. Ishii, Yoshinori Kitagawa, Takayuki Miyazawa, Daniel R. Salomon, Robin A. Weiss, and Clive Patience, please see:



Associate Professor Daniel Salomon is one of the authors on a recent paper that helps clarify the risks of pig to human transplantation. Photo by Biomedical Graphics.