By David N. Leff

What is a mysterious retrovirus called HERV-W doing in a nice tissue like the human testis?

Molecular biologist John McCoy, then at Genetics Institute Inc. in Cambridge, Mass., asked this question last year when he and his colleagues discovered that unknown viral sequence in human testicular cells. His answer, to this day: "We have no idea."

The thing that got McCoy interested, he recalled, "was what a retroviral envelope (RVE) protein might be doing in a human testis library. This was quite unusual. There are lots of examples in the literature of viruses picking up human genes for their own nefarious purposes. For example, to try and control the immune system, or downregulate host defense mechanisms.

"It's unusual to find an RVE gene product expressed in a human host," McCoy observed. "We were intrigued that maybe this meant that the reverse had happened: That at some point in evolutionary history the human host had actually picked up a viral gene - presumably a bad thing to catch - and was now using it for some important piece of biology, which had been subverted to do something important for the human host. That hasn't happened too many times before. One example is a mouse strain that picked up a strain of virus enabling those mice to become resistant to further viral infections.

"The RVE we cloned had no known function," he went on. "That in itself was sort of uncommon. If you find pieces of ancient retroviruses integrated into the human genome, that's not at all surprising; there are huge numbers of them. What is surprising is to find - as we did - that at least a portion of the HERV-W virus apparently is still operational. And its protein, syncytin, is one of the structural components of the virus envelope.

"We subsequently found that this gene was most abundantly expressed - at least 10, 20, 50 times more abundantly - in placenta than in testis. The molecule we cloned out of testis was the same one that we found in placental tissue. We haven't fully proven it yet, but now there's pretty good suggestive evidence that this retroviral protein is importantly implicated in placental development, and possibly in placental diseases, such as preeclampsia or choriocarcinoma."

Captured Viral Protein Linked To Placental Ills

McCoy is senior author of a paper in the current issue of Nature, dated Feb. 17, 2000, titled "Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis." (He has recently moved from Genetics Institute to Biogen Inc., also in Cambridge, where he is director of molecular technologies in the firm's genomics program.)

"When retroviruses integrate into the genome," McCoy told BioWorld Today, "they very often replicate multiple times. There are maybe 10 or 20 copies of defective syncytia genes scattered throughout the genome. Currently, we think the active one in on the long arm of human chromosome seven."

He continued: "Syncytin, the protein that gene expresses, sits on the outer membranes of these fused cells that are part of the placental structure, called syncytial trophoblast. The actually boundary layer between the maternal blood circulation and the fetal tissue," he explained, "is composed of cells between which all the boundaries have broken down, and this fused layer is called the syncytial trophoblast. That's where syncytin is expressed.

"There are many reasons why fusing cells together might be a good idea," McCoy continued. "One of the great mysteries of placental biology is why the mother doesn't reject her baby, since half the genes in the fetus aren't coming from the mother, but from the father. Ordinarily, you'd think it is being rejected, but it isn't." (See BioWorld Today, Jan. 20, 2000, p. 1.)

"Lots of RVE proteins," McCoy pointed out, "carry sequences that are thought to suppress the host's immune systems, and syncytin has one of these segments. It's a short 25-amino-acid region. For instance, when HIV infects T cells, it causes them to fuse.

"At this point we don't know if our findings have any clinical potential," McCoy said, "because we haven't delved deeply into the central pathologies. But it is possible," he speculated, "that there are some major placental diseases - preeclampsia being the major one - where it's thought that defects within the cell fusion can lead to the disease. We have some of this data, which will be the subject of a future paper. All this work is being done at Genetics Institute; it will not be ongoing at Biogen.

"If it turns out that syncytin is a causative agent in placental pathology," McCoy went on, "then drugs aimed at modulating the protein's activity in vivo would be viable therapeutics. But that's like years of research away."

Antibody To - Speculative - Rescue

Choriocarcinoma is a trophoblast disease. Fetal trophoblast cells get into the maternal circulation and grow to cause hemorrhagic, metastatic tumors. "Our observations in vitro," McCoy recounted, "showed that when we express syncytin, we downregulate proliferation. So it's possible that syncytin expression is important to control trophoblastic invasiveness. But if you get disregulation, you may end up with enhanced trophoblast invasion, which may be one of the causal reasons behind choriocarcinoma. But that's pure speculation.

"We did develop an antibody to syncytin," McCoy recounted, "and asked whether we could induce choriocarcinoma cell lines to fuse in response to upregulation of the protein, and could we reverse that by addition of that neutralizing antibody to syncytin, which was what we did.

"The whole area of functional genomics," McCoy concluded, "is very hot and topical right now: How do you find a gene sequence and work back to its function? This reverse-genetics area, which we're doing now, is part of the Human Genome Project."