The aim of this project is to establish in rodents the immunogenicity of novel vaccine carriers based on E1-deleted chimpanzee serotypes of adenovirus that do not circulate in the human population. The purpose of this project is threefold: [1] We wish to characterize aspects of the immune responses to the transgene products expressed by the novel vaccines that are related to the carrier rather than the inserted HIV-1 sequences. These studies include: [a] The magnitude of the immune responses in relation to vaccine dose and route of application; [b] The type of the induced immune response (Th1/Th2); [c] Anatomic distribution of effector or memory T1 cells (central versus mucosal) depending on the route of immunization; [d] Potential interference by pre-existing immunity to unrelated common human serotypes of adenovirus; [e] The effect of heterologous prime boost regimens; [f] The longevity of the response [g] Characteristics of the initial vaccine-induced inflammatory response. These experiments, that address characteristics of the vaccine carrier, will be conducted for T cell responses with simple constructs expressing a codon-optimized truncated form of gag (p37) derived from the consensus sequence of clade B. B cell responses will be analyzed with a construct expressing gp140 of a reference strain of clade B. [2] In preparation for clinical trials, we will test the pertinent immune responses (mainly CD8+ T cell responses to the gag, pol and nef and antibody responses to gp140 of env) using constructs expressing codon-optimized sequences of HIV-1 reference strains of clades B and C. [3] Additional constructs will express sequences from SIV for studies in primates. Prior to initiating these costly studies, we will test the construct under optimized conditions briefly for induction of immune responses (CD8+ T cells) in rodents.
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