1. Field of the Invention
Retroviruses are enveloped viruses which bear glycoprotein spicules encoded by the viruses, at their surface. These envelope glycoproteins are synthesized in the form of polyprotein precursors (Pre-env) which are then cleaved by cellular proteases into mature surface (SU) protein and into transmembrane (TM) protein. Envelope glycoproteins are involved in the entry of viruses into host cells. They specifically recognize and bind to cell surface receptors and are necessary for the fusion of the viral envelope and the cell membranes of the host. The receptor and the envelope are multimeric or oligomeric molecules. For all enveloped viruses, the interactions of the envelope glycoproteins with the cellular receptor(s) lead to conformational rearrangements of the envelope required for exposure of the fusion peptide. The fusion takes place at the surface of the cell or in cellular vesicles, depending on the pathway of endocytosis of the virion. In addition, in order to allow entry of the virus, fusion mediated by the viral surface proteins may, under certain conditions, cause cell-to-cell fusion, resulting in the formation of giant multinucleated cells or syncytia. The formation of syncytia takes place via at least two pathways: a virion may simultaneously fuse with two cells, in which case reference is made to fusion “from without”, or an infected cell which expresses the envelope glycoproteins at its surface may fuse with an adjacent cell (fusion “from within”).
2. Description of Related Art
The envelope determinants and the sequence of events causing the conformational changes in the envelope during the processes of fusion “from without” are well documented for orthomyxoviruses which require an acid environment in the endocytosis vesicles in order to enter (Skehel, J. J. et al., PNAS, 79:968-972 (1982)). For retroviruses, for which the pathway of entry is independent of the pH, the precise determinants and steps leading from the recognition of the receptor to the activation of the fusion have not yet been elucidated. Other retroviruses are known to induce cell-to-cell fusion (“fusion from within”), such as the feline leukemia virus, the mouse mammary tumor virus, the avian reticuloendotheliosis virus, HIV and SIV.
Moreover, Fefferey S. Jones and Rex Risser (Journal of Virology, January 1993, p. 67-74) have shown that the envelope glycoproteins of the wild-type ecotropic murine leukemia virus (MuLV), under the control of the viral LTR, are capable of inducing the formation of syncytia in rat XC cells in the absence of virions (fusion “from within”).
To the inventors' knowledge, the envelope glycoproteins of a human endogenous retrovirus have never been shown to have fusogenic power in a process of fusion “from within”.
Some authors have indeed put forward the hypothesis that the endogenous retroviral envelope of ERV3, a human endogenous retrovirus close to MLV (Moloney leukemia virus), may be involved, in vivo, in the development of the placenta via a process of fusion (Patrick J. W. Venables et al., Virology, 211, 589-592 (1995)), but this phenomenon has never been demonstrated in vitro. Furthermore, studies on the polymorphism of ERV3 env on individuals of Caucasian origin, have made it possible to demonstrate the presence of a mutation in the (SU) region of the ERV3 envelope, generating an early stop codon present in the homozygous state in 1% of the population studied, without these individuals exhibiting any abnormality of pregnancy or of placental development (Nathalie de Parseval and Thierry Heidmann, Journal of Virology, Vol. 72, No. 4, pages 3442-3445 (1998)), this casting doubt over the hypothesis previously put forward.