A tumor necrosis factor receptor family protein serves as a cellular receptor for the macrophage-tropic equine lentivirus

Characterization of cellular receptors for human, simian, and feline immunodeficiency viruses that are tropic for lymphocytes and macrophages have revealed a common theme of a sequential binding of viral envelope proteins with two coreceptors to mediate virus infection of target cells. In contrast to these dual tropic immunodeficiency viruses, the ungulate lentiviruses, including equine infectious anemia virus (EIAV), exclusively infect cells of the monocyte-macrophage lineage to cause progressive degenerative diseases without clinical immunodeficiency. EIAV causes a uniquely dynamic disease that is characterized by recurrent disease episodes including fever, diarrhea, lethargy, anemia, and thrombocytopenia. Although EIAV provides an important animal model for lentivirus disease resulting from macrophage infection, to date there has been no definition of the specific cellular receptor(s) used by the equine lentivirus to infect target cells. In the current study, we have identified and cloned a functional receptor for EIAV, designated equine lentivirus receptor-1 (ELR1), related to the family of TNF receptor (TNFR) proteins. ELR1 was shown to be expressed in various equine cells permissive for EIAV replication in vitro, including monocytes and macrophages. In contrast, EIAV-resistant human, murine, and simian cells were negative for ELR1 expression but became susceptible to virus infection when transduced with a recombinant murine retrovirus expressing the ELR1. Thus, these results identify a specific functional receptor for a macrophagetropic lentivirus and indicate that infection by EIAV may be mediated by a single receptor, in contrast to coreceptors used by the lymphotropic immunodeficiency lentiviruses.