Significant progress has been made toward defining the mechanisms of immune control of lentiviral infections, and it is evident that viral specific CTL and CD4+ helper T lymphocytes are critically important in limiting lentiviral replication. However, correlates of T lymphocyte-mediated protection are still not known. Specific knowledge gaps include how to induce and support a protective CTL response in the face of CD4+ T lymphocyte deficiency, the specific epitopes that must be recognized by CTL to control lentivirus replication, and the qualitative characteristics (i.e. functional avidity) of protective CTL. The overall goal of the proposed research is to delineate the requirements of CTL-mediated protection against lentiviral infection in a CD4+ T lymphocyte deficient environment. The lentiviral system under study is EIAV in horses. Most horses control EIAV replication within a year and remain persistently infected unapparent carriers. Results of EIAV infection in Arabian foals affected with SCID, as well as immune reconstitution with viral-specific T and B-lymphocytes in a SCID foal prior to EIAV challenge, indicate that this control of viral replication is mediated by a viral-specific immune response. Since the equine SCID defect occurs naturally in the host species in which EIAV causes disease, this lymphocyte deficient model system provides an opportunity to dissect the correlates of lentiviral immunity in a rigorous way that is unavailable in any other lentiviral model system. In particular, CD8+ CTL can be transferred into SCID foals and evaluated in the absence of CD4+ T lymphocytes. The experiments outlined in this proposal will dissect the avidity requirements for CTL-mediated protection against EIAV in SCID foals by adoptive transfer of EIAV Rev-specific CTL clones supported with exogenous IL-2 administration. The CTL clones will target a highly conserved region of the Rev protein. It is anticipated that a high avidity CTL clone specific for this nonvariable Rev epitope will be protective without selecting for escape variants. In contrast, protection is not expected following adoptive transfer of a low avidity CTL clone with the same specificity. Accomplishing these aims should help define the correlates for CTL protection against a lentivirus challenge in a CD4+ T lymphocyte-deficient environment, in terms of epitope specificity, avidity, and viral escape. The information obtained from the proposed studies should have implications for HIV-1 immunotherapy and vaccine design, where experiments of this type may be more difficult. ? ?
