14 DAY TRIAL // Remnants of ancient viral infections are found in the genomes of many species, including all mammals and humans. The genetic material that a virus leaves behind can disrupt genes causing cancer or diseases, but usually is harmless and sometimes it proves beneficial, providing protection from infection or being involved in reproduction.
In particular, a class of retroviruses, known as endogenous retroviruses (enJRVSs ) related to Jaagsiekte sheep retrovirus ( JSRVs ), are critical during the early phase of pregnancy when the placenta begins to develop, as a team of US and Scottish scientists has discovered on sheep.
Retroviruses are best known for their ability to cause diseases (e. g. HIV or JSRVs which provoke lung cancer on sheep). They are unique for their ability to permanently insert their genetic DNA into the DNA of host cells, said Thomas Spencer, a reproductive biologist with the Texas Agricultural Experiment Station and Texas A&M University. During mammalian evolution, some retroviruses infected the reproductive cells of the host, which is then inherited by their offspring. Many scientists believed these endogenous retroviruses were junk DNA, Spencer said.
The idea that endogenous retroviruses are important for reproduction in mammals has been around for about 30 years, Spencer said. Studies in cultured cells have shown that a protein of a human endogenous retrovirus might have a role in the development of the human placenta.
The team blocked expression of the envelope protein of the enJSRVs using morpholino antisense oligonucleotides, which inhibit translation of specific messenger RNA, into sheep uteruses 8 days after fertilization--6 to 8 days before the placenta begins to form. By the 16th day after fertilization, the treated embryos were already smaller and more fragile than controls that were treated with random DNA fragments. None of the five treated embryos' placentas formed properly, and all but one died by day 20. The growth of the placenta was reduced and a certain cell type, termed giant binucleate cells, did not develop.
The result was that embryos could not implant and the sheep miscarried, Spencer said. Miscarriage is a serious medical problem for all mammals, including humans.
"Our research supports the idea that endogenous retroviruses shaped the evolution of the placenta in mammals and then became indispensable for pregnancy, and thus may be why they are expressed in the placenta of many mammals," he said.
"The enJSRVs arose from ancient infections of small ruminants during their evolution," said. Dr. Massimo Palmarini, a virologist at The University of Glasgow Veterinary School. "This infection was beneficial to the host and was then positively selected for during evolution. In other words, animals with enJSRVs were better equipped than those without. Therefore, enJSRVs became a permanent part of the sheep genome and, in these days, sheep can't do without them."
The placenta forms when cells in the outermost layer of the embryo fuse with those lining the walls of the uterus. In many mammals, the placenta is loaded with certain viral envelope proteins, leading scientists to suspect that these proteins may be essential for its development. Indeed, experiments done with human and mouse cells in culture show that these proteins can make cells fuse with each other, suggesting that they may be responsible for the fusion of cells in the developing placenta.
"This is the first study done within animals that strongly supports the idea that endogenous retroviruses have become essential for placental development and thus successful reproduction of some mammals" says Spencer, whose team reports its work online this week in the Proceedings of the National Academy of Sciences (PNAS). "Because similar viruses are present in the placentas of a wide range of mammals, including humans, the placenta might have evolved multiple times during evolution with different viruses playing a role", says study author and veterinary pathologist Massimo Palmarini of the University of Glasgow Veterinary School in the U.K.
Until this study, there were only "correlations and suspicion" that viral gene products could be involved in the development of the placenta, but nothing had been proven, says R. Michael Roberts, a developmental biologist at the University of Missouri, Columbia. Spencer hopes that future studies will reveal exactly how the envelope protein regulates the growth and development of the placenta, with implications for both human health and animal production.