Human endogenous retroviruses (HERVs) constitute 8% of the human genome and are involved both in pathologies and in nonpathological phenomena.
The human endogenous retrovirus family W (HERV-W) is derived from an infectious retroviral element that was integrated into the germ line 25 to 40 million years ago. The HERV-W envelope protein, also called syncytin, is a fusogenic glycoprotein involved in the formation of the syncytiotrophoblastic layer of the placenta. It is encoded by the env gene of the proviral locus ERVW1 and synthesized in the form of a gPr73 precursor which is specifically cleaved into two mature proteins, a surface subunit gp50 (SU) and a transmembrane subunit gp24 (TM).
In vitro, syncytin of the HERV-W family induces a cell to cell fusion that is dependent on its interaction with a receptor-transporter of amino acids of the ASCT family (h-ASCT2, hASCT1). Phylogenic studies then showed that syncytin is related to a group of retroviruses comprising in particular the cat endogenous virus RD114, the monkey endogenous virus BaEV, simian retroviruses and avian retroviruses: avian reticuloendotheliosis virus REV-A and spleen necrosis virus SNV, all having in common the type 2 sodium-dependant neutral amino acid receptor-transporter or hASCT2 (Rasko et al, 1999, Proc. Natl. Acad. Sci. USA Vol. 96, pp. 2129-2134; Tailor et al, 1999 Journal of Virology, vol. 73(5) May 1999, P. 4470-4474). Thus, the infection of cells with viruses of this retrovirus group leads to a specific reduction in the transport of amino acids (Rasko et al., 1999). The infection of a cell with one of these retroviruses (or the expression of one of these envelopes in the cell) prevents, through interference (interaction) in relation to a receptor of the ASCT family, the infection of this same cell by another of these retroviruses or the fusion with another cell expressing another envelope. Through interference in relation to a receptor of the ASCT family, the infection of a cell by one of these retroviruses prevents the infection by another of these retroviruses. All these retroviruses belong to the same HERV-W virus interference group.
The mechanisms of binding between the envelope and the ASCT receptor remain obscure, and to date no domain for binding to an ASCT receptor has been identified and defined either in the SU of the HERV-W envelope protein or in the SUs of retroviruses of the same interference group. This theme is nevertheless essential since the inhibition of the envelope/ASCT receptor interaction would in addition make it possible to prevent the entry of a retrovirus into the cell, and therefore to block its replication cycle, to block the phenomenon of envelope/ASCT receptor interaction and/or of cell fusion which may be involved in the formation of tumors, in the proliferation of metastasic cells or in drug resistance phenomena (see by way of illustration the publication “Cell fusion: A hidden enemy?, Cancer Cell: May 2003, vol. 3), to block the phenomenon of envelope/ASCT receptor interaction and/or of cell fusion which may be involved in nervous system diseases and even to inhibit the cell-cell fusion involved in trophoblastic differentiation (contraceptive vaccination). Furthermore, the inhibition of the envelope/hASCT receptor interaction could prevent tumor propagation by counteracting a local immunosuppression which may result from the envelope/hASCT receptor interaction. Indeed, it has been shown, on the one hand, that the infection of cells with viruses of this retrovirus group (in particular those inducing immunodeficiencies) leads to a specific reduction in the transport of amino acids (Rasko et al, PNAS, vol. 96. pp 2129-2134 (1999)), and on the other hand, a direct link is proposed between the impairment of the transport of amino acids and immunosuppression (Espinosa A, Villarreal L P., T-Ag inhibits implantation by EC cell derived embryoid bodies. Virus Genes. 2000; 20(3): 195-200; JE, Battini J L, Gottschalk R J, Mazo I, Miller A D., The RD114/simian type D retrovirus receptor is a neutral amino acid transporter. Proc Natl Acad Sci USA, 1999, Mar. 2; 96(5): 2129-34). Thus, as regards nervous system diseases, it is known that the hASCT receptors are involved in the specific transport of neutral amino acids and that neuronal cells, for the transmission of information, predominantly use neuromediators of a polypeptide nature. Thus, the binding of the Env-HERV-W protein to receptors which normally have to transport the amino acids required for the synthesis of neuromediators can affect the capacity of the neurons to synthesize the neuromediators by reducing the entry of the physiological agonists such as amino acids via the ASCT receptors. Moreover, if neurons whose intercellular networks form connections which are essential for the transmission of information circulating in the brain and the spinal cord, form syncytia following a fusion of several neurons which is induced by the Env-HERV-W protein, all the networks for transmission of information become disrupted and connected to the same fused “cellular package” and, furthermore, the neuromediator production activity of each cell is no longer individualized or connected to the upstream or downstream conduction pathways (dendrites and axons) which are specific to it.