Equine infectious anemia virus (EIAV) is a macrophage-tropic lentivirus that rapidly induces disease in experimentally infected horses. Because EIAV infection and replication is centered on the monocyte/macrophage and has a pronounced acute disease stage, it is a useful model system for understanding the contribution of monocyte/macrophages to other lentivirus-induced diseases. Genetic mapping studies utilizing chimeric proviruses in which parental viruses are acutely virulent or avirulent have allowed the identification of important regions that influence acute virulence. U3 regions in the viral LTR, surface envelope (SU) protein and the accessory S2 gene strongly influence acute disease expression. While the chimeric proviruses provide insight into genes or genome regions that affect viral pathogenesis, it is then necessary to further dissect those regions to focus on specific virus-host mechanisms that lead to disease expression. The V6 region of the viral env protein is an example of one identified region that may interact with the ELR-1 receptor in an important way and we are currently identifying S2 protein motifs required for disease expression.