The IAPE (Intracisternal A-type Particles elements with an Envelope) family of murine endogenous retroelements is present at more than 200 copies in the mouse genome. We had previously identified a single copy that proved to be fully functional, i.e. which can generate viral particles budding out of the cell and infectious on a series of cells, including human cells. We also showed that IAPE are the progenitors of the highly reiterated IAP elements. The latter are now strictly intracellular retrotransposons, due to the loss of the envelope gene and re-localisation of the associated particles in the course of evolution. In the present study we searched for the cellular receptor of the IAPE elements, by using a lentiviral human cDNA library and a pseudotype assay on transduced cells. We identified Ephrin A4, a GPI-anchored molecule involved in several developmental processes, as a receptor for the IAPE pseudotypes. We also found that the other 4 members of the Ephrin A family –but not those of the closely related Ephrin B family- were also able to mediate IAPE cell entry, thus significantly increasing the amount of possible cell types susceptible to IAPE infection. We show that these include mouse germline cells, as illustrated by immunohistochemistry experiments, consistent with IAPE genomic amplification by successive re-infection. We propose that the uncovered properties of the identified receptors played a role in the accumulation of IAPE elements in the mouse genome, and in the survival of a functional copy.
In mammals, nearly half the genome is composed of reiterated scattered sequences. Some of them, called endogenous retroviruses, have a structure similar to that observed for the integrated form of infectious retroviruses. The current theory to account for their presence is that an infectious retrovirus once infected the germline of its host. This viral genome was then transmitted to the progeny and expressed from there, producing new infectious particles, which could re-infect new germline cells and thus increase the viral genomic copy number. However no evidence has yet been provided to support this model. In this study, we identify a family of five cellular proteins, the Ephrin As, as receptors for a model mouse family of endogenous retroviruses, the IAPE elements. We analyse their expression pattern and show that both the oocytes and some male germline cells express Ephrin A proteins and can thus be infected by IAPE particles. This finding strongly supports the current model of ERVs amplification. In addition, the IAPE envelope ability to use five different cellular receptors suggests that it might be impossible for the host to evolve a resistance against this viral element, and provides a clue on how the IAPE family survived so long in the mouse genome.