The goals of the research proposed in Project I are to construct herpes simplex virus vectors that express simian immunodeficiency virus (SIV) proteins and to analyze the properties of these vectors in cell culture and in mice. We have shown previously that replication-defective mutants and attenuated replication-competent strains of herpes simplex virus type 1 (HSV-1) can immunize mice against disease and infection upon subsequent challenge by virulent wild type herpes simplex virus, demonstrating that these mutant viruses are effective vaccines in mice against HSV. We have also shown that HSV recombinant strains induce a TH1 like helper T cell response against HSV antigens and against a foreign antigen expressed from a recombinant HSV strain.
Our specific aims are to 1) Construct replication-competent, latency- competent HSV-1 strains that express SIV envelope protein or SIV envelope + gag/pol from an endogenous viral promoter or heterologous promoter and characterize expression of SIV proteins in culture and cells. 2) Construct and characterize replication-competent, latency-defective HSV-1 strains that express SIV proteins. 3) Construct and characterize replication-defective strains of HSV-1 that express SIV proteins. 4) Determine the immunogenicity of these viral vectors in mice by determining the level and type of humoral response and the types of T cell responses, and to determine the mechanism of induction of these responses. These viral vector strains will be utilized in the project by Ronald C. Desrosiers for the purposes of immunization off rhesus monkeys. The ultimate goal of these studies is to determine the parameters that induce optimal protective immunity in rhesus monkeys against SIV and to determine whether herpesviruses can provide an effective vaccine vector system for induction of immunity against AIDS.
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