The definitive correlates for immune protection against lentiviruses have not yet been defined; although CTL are one critical component. This conclusion is based on the temporal association between viremia control in lentiviral infections and the appearance of CTL, and on other correlations between CTL and low HIV-1 loads. Further, depletion of CD8+ cells in SIV-infected monkeys with controlled virus levels results in viremia, and depletion of these cells during acute infection results in a failure to control the initial viremia. Despite the need for CTL in any preventive vaccine for HIV-1, there is a gap in knowledge about how to induce requisite numbers of CTL memory cells to epitopes on multiple proteins in populations of individuals with disparate MHC class I molecules. CTL are associated with control of primary viremia in equine infectious anemia virus (EIAV)-infected horses, and later, in carrier horses. CTL occur to epitopes on EIAV Gag, Pol, Env, Rev, and regulatory protein S2, and the goal is to induce CTL in naive horses. Optimal results would be CTL to epitopes on multiple EIAV proteins in horses with diverse haplotypes and one strategy is to target dendritic cells with a lentivirus vector that produces EIAV proteins which enter the MHC class I processing pathway. Recent preliminary data demonstrate that EIAV infects dendritic cells in addition to known infection of macrophages and endothelial cells. Therefore, the plan is to use an EIAV vector to induce CTL in naive horses which will use EIAV Env to target dendritic cells required for a primary immune response and also to target other antigen presenting cells (APC). The EIAV vector is designed to express Gag, Pol and Tat proteins in transduced APC, but not Env. This is because the Env protein made in the packaging cells for vector envelope is from RNA lacking a packaging signal to help assure that vector-transduced cells will not produce infectious virus. Even though there are safety concerns with lentivirus vector use in humans, effective induction of CTL in horses to EIAV proteins with an EIAV vector targeting dendritic cells would be a novel observation and would stimulate further research on other types of vectors to target human APC. Thus, this proposal will test the hypothesis that targeting dendritic cells in vivo with an EIAV vector will induce CTL in horses to multiple viral proteins.
