A vaccine that is able to target HIV proteins to the class I restricted pathway of antigen recognition could be a powerful prophylactic and possibly therapeutic agent for HIV infections. Antigens secreted by Listeria monocytogenes, a gram-positive bacterium that can grow within the cytoplasm of macrophages and adjoining cells, will have direct access to the MHC class I pathway to cytotoxic T cells. Previous studies have established that recombinant Listeria have the capacity to express foreign antigens and can be used to successfully protect mice against infection and tumor cell challenge. However, infection by L. monocytogenes, while rare and controlled by antibiotics, can cause serious illness, particularly in immune suppressed or pregnant patients. For these reasons, experiments are proposed to develop a hyper- attenuated strain of L. monocytogenes as an HIV/SIV vaccine vector. In preliminary studies the investigator has isolated a strain of L. monocytogenes that is unable to synthesize D-alanine, an amino acid required for the synthesis of the cell wall. The use of this hyper- attenuated L. monocytogenes will form the foundation for the following experimental aims:
Specific Aim 1 : To develop a hyper-attenuated strain of L. monocytogenes expressing HIV/SIV proteins.
Specific Aim2 : To evaluate the ability of the attenuated strains to deliver HIV/SIV DNA vaccines.
Specific Aim 3 : To optimize the cell mediated immune response in mice to HIV/SIV antigens expressed or delivered by the attenuated strains.
Specific Aim 4 : To examine a human model of antigen presentation: to access the ability of infected PBMCs to expand patient HIV-1-specific CTLs.
