Research Proposal: The long-term goal of this research is to define the role of CTLs in the control of EIAV, a lentivirus of horses which cause a persistent infection characterized by recurrent episodes of viremia with concurrent fever, thrombocytopenia, and anemia. Horses infected with EIAV eventually control the viremia and associated clinical disease, and remain lifelong inapparent carriers. Work using foals affected with severe combined immunodeficiency (SCID) has shown that lymphocyte responses are required to terminate the viremia following acute infection. In addition, continued immunologic control mechanisms are likely responsible for maintenance of the inapparent carrier state, as evidenced by recrudescence of clinical disease following immunosuppression. The fact that EIAV- specific CD8+ CTLs are detected con-incident with the termination of the initial viremia following acute infection, prior to the appearance of neutralizing antibody, suggests that CTLs are involved in control of viremia. In addition, inapparent carriers have EIAV-specific CTLm in PBMC. The proposed research will test the hypothesis that EIAV-specific CD8+ CTLs will prevent or reduce viremia following EIAV challenge. In the specific aims, Env and Gag/Pr-specific CD8+ CTLs from PBMC from inapparent carriers will be selected, stimulated and expanded using retroviral vector-transduced autologous equine kidney stimulator cells, and adoptively transferred to ELA-A matched SCID foals. These foals will then be infected with EIAV and the protective effects determined. If the foals are protected, the protective effects of CD8+ CTLs specific for the conserved Gag proteins p15, p26a, and p26b will be evaluated. The results of this research should provide insight into the mechanisms of immune control of other lentiviral infections, including HIV-1.
