Infection with live attenuated simian immunodeficiency virus (SIV) can protect adult monkeys against a subsequent infection with virulent SIV. Both, the antibody and cytotoxic T lymphocyte (CTL) responses are probably necessary for protection, and to date all protective immunity has been associated with persistence of vaccine virus. Currently, a major goal of vaccine research is to understand the essential features of protective immunity engendered by live attenuated SIV and to safely recreate it in a clinically acceptable formulation. This proposal is for a preliminary investigation of a novel vaccine approach for persistent presentation of SIV antigen to CTL in vivo. An attenuated herpes simplex virus expressing SIV gag will be generated; the ability of this vector to induce a CTL response and to establish latent infection in rhesus monkeys will be established. HSV normally encodes a protein, ICP47, which blocks TAP, the transporter associated with antigen processing - and interferes with antigen presentation to CTL. SIV mac 251 gag coding sequences will be introduced into an HSV which has been engineered to lack ICP47; and a rescue virus then created which expresses functional ICP47. These two viruses will be used to immunize rhesus monkeys expressing the MHC class I alleles MamuA01, and the CTL responses to the immunodominant gag epitope pcll will be compared quantitatively and qualitatively with those induced by recombinant vaccinia virus expressing SIV gag. Immunized animals will be challenged intravenously with SIV mac251; and virus load assessed by virus isolation and branched DNA amplification of plasma viral RNA. Control challenge groups will include unimmunized animals and animals immunized with vaccinia and HSV vectors alone. At necropsy, the extent of virus latency in dorsal root ganglia established by HSV with and without functional ICP47 will be assessed.
