PERV Receptors Found in Humans
By Jason Socrates
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: http://www.pnas.org/cgi/content/abstract/1138025100v1.
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.