Many mammalian viruses have acquired genes from their hosts during their evolution1. The rationale for these acquisitions is usually quite clear: the captured genes are subverted to provide a selective advantage to the virus. Here we describe the opposite situation, where a viral gene has been sequestered to serve an important function in the physiology of a mammalian host. This gene, encoding a protein that we have called syncytin, is the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W2. We find that the major sites of syncytin expression are placental syncytiotrophoblasts, multinucleated cells that originate from fetal trophoblasts. We show that expression of recombinant syncytin in a wide variety of cell types induces the formation of giant syncytia, and that fusion of a human trophoblastic cell line expressing endogenous syncytin can be inhibited by an anti-syncytin antiserum. Our data indicate that syncytin may mediate placental cytotrophoblast fusion in vivo, and thus may be important in human placental morphogenesis.

Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis.

The carcinogen-induced rat mammary carcinoma model, developed a quarter of a century ago by Dr. Charles Brenton Huggins, is today the standard laboratory animal model in the study of human breast cancer. This model has a number of features that make it particularly attractive to the experimental oncologist, e.g., tumor induction ease and reliability, organ site specificity, tumors of ductal origin, tumors of predominantly carcinomatous histopathological characteristics, tumors of varying growth factor and/or hormone responsiveness, and the potential to examine tumor initiation and promotion processes. Since the development of this model, an extensive literature describing the biological behavior and responsiveness of these tumors has been provided. The purpose of this communication is to condense, summarize, and integrate this vast literature into a single review with the intent on facilitating information acquisition and conceptualism by both the new and the established experimental oncologist. In addition, and equally important, this communication is a tribute to Dr. Huggins, whose pioneering efforts in the development of this model and whose scientific contributions and dedication to the oncological sciences in general have made an important and lasting impact on us all.

https://cancerres.aacrjournals.org/content/canres/45/8/3415.full.pdf

Host Factors Affecting the Growth of Carcinogen-induced Rat Mammary Carcinomas: A Review and Tribute to Charles Brenton Huggins

Retroelements constitute a large portion of our genomes. One class of these elements, the human endogenous retroviruses (HERVs), is comprised of remnants of ancient exogenous retroviruses that have gained access to the germ line. After integration, most proviruses have been the subject of numerous amplifications and have suffered extensive deletions and mutations. Nevertheless, HERV-derived transcripts and proteins have been detected in healthy and diseased human tissues, and HERV-K, the youngest, most conserved family, is able to form virus-like particles. Although it is generally accepted that the integration of retroelements can cause significant harm by disrupting or disregulating essential genes, the role of HERV expression in the etiology of malignancies and autoimmune and neurologic diseases remains controversial. In recent years, striking evidence has accumulated indicating that some proviral sequences and HERV proteins might even serve the needs of the host and are therefore under positive selection. The remarkable progress in the analysis of host genomes has brought to light the significant impact of HERVs and other retroelements on genetic variation, genome evolution, and gene regulation.

https://www.pnas.org/content/pnas/101/suppl_2/14572.full.pdf

Retroelements and the human genome: New perspectives on an old relation

The Epstein-Barr virus.

We recently demonstrated that the product of the HERV-W env gene, a retroviral envelope protein also dubbed syncytin, is a highly fusogenic membrane glycoprotein inducing the formation of syncytia on interaction with the type D mammalian retrovirus receptor. In addition, the detection of HERV-W Env protein (Env-W) expression in placental tissue sections led us to propose a role for this fusogenic glycoprotein in placenta formation. To evaluate this hypothesis, we analyzed the involvement of Env-W in the differentiation of primary cultures of human villous cytotrophoblasts that spontaneously differentiate by cell fusion into syncytiotrophoblasts in vitro. First, we observed that HERV-W env mRNA and glycoprotein expression are colinear with primary cytotrophoblast differentiation and with expression of human chorionic gonadotropin (hCG), a marker of syncytiotrophoblast formation. Second, we observed that in vitro stimulation of trophoblast cell fusion and differentiation by cyclic AMP is also associated with a concomitant increase in HERV-W env and hCG mRNA and protein expression. Finally, by using specific antisense oligonucleotides, we demonstrated that inhibition of Env-W protein expression leads to a decrease of trophoblast fusion and differentiation, with the secretion of hCG in culture medium of antisense oligonucleotide-treated cells being decreased by fivefold. Taken together, these results strongly support a direct role for Env-W in human trophoblast cell fusion and differentiation.

Direct Involvement of HERV-W Env Glycoprotein in Human Trophoblast Cell Fusion and Differentiation

C-Type Particles in Normal Human Placentas

The major envelope glycoprotein (gp71) purified from Rauscher leukemia virus (R-MuLV) binds efficiently to murine lymphoid cells but not to either murine nonlymphoid cells or lymphoid cells from other species. Binding of 125I-labeled R-MuLV gp71 was competitively inhibited by unlabeled glycoprotein, as well as by whole R-MuLV, but not by murine xenotropic viruses, R-MuLV p30, and several unrelated proteins. Polyacrylamide gel electrophoresis profiles of iodinated gp71 after binding to lymphoid cells were similar to prebound profiles. Antibody to R-MuLV gp71 prevented binding, whereas normal serum had no effect. Adsorption of the glycoprotein to murine lymphoid cells occurs rapidly and is time and temperature dependent. The procedure described is sensitive for detecting the binding activity of approximately 10(4) cells. Binding was proportional up to 2.5 X 10(5) cells per ml and plateaued above 10(7) cells per ml. In the presence of excess R-MuLV gp71, BALB/c thymocytes bound approximately 2.4 X 10(4) molecules per cell.

Binding characteristics of Rauscher leukemia virus envelope glycoprotein gp71 to murine lymphoid cells.

Ultrastructural Comparison of Placental Virus With Several Type-C Oncogenic Viruses

C-type particles are found in human, baboon, marmoset, rhesus, patas, and cynomolgus monkeys A cebus monkey and two chimpanzee placentas have failed thus far to show the presence of these particles Of the nonprimate tissues examined one mouse and one guinea pig placenta were positive whereas a rabbit placenta was negative Variations in number of particles present in tissues as well as number of animals of a given species containing particles are noted The isolation of foamyviruses from placenta cultures makes critical evaluation and interpretation of findings imperative Several considerations suggest that the presence of foamyviruses is coincidental

A comparative study on the presence of C-type viral particles in placentas from primates and other animals.

Freeze-thaw preparations of banded Rauscher murine leukemia virus markedly suppressed the in vitro cellular-mediated blastogenic response of murine splenic lymphocytes to phytohemagglutinin-P and to allogeneic cells in two-way mixed-leukocyte reaction. Suppression was shown not to be due to cytotoxicity or to virus-mitogen binding. It is suggested that a virion envelope component interferes with cellular-mediated immunity by altering cell recognition sites.

A. Hellman

Papers

C-Type Particles in Normal Human Placentas

Binding characteristics of Rauscher leukemia virus envelope glycoprotein gp71 to murine lymphoid cells.

Ultrastructural Comparison of Placental Virus With Several Type-C Oncogenic Viruses

A comparative study on the presence of C-type viral particles in placentas from primates and other animals.

Inhibition of Lymphocyte Transformation by Disrupted Murine Oncornavirus