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.
|Li, Zhongxia; Zhang, Manxin; Zhou, Chenghui et al. (2008) Novel vaccination protocol with two live mucosal vectors elicits strong cell-mediated immunity in the vagina and protects against vaginal virus challenge. J Immunol 180:2504-13|
|Li, Zhongxia; Zhao, Xinyan; Zhou, Chenghui et al. (2006) A truncated Bacillus subtilis dal gene with a 3' ssrA gene tag regulates the growth and virulence of racemase-deficient Listeria monocytogenes. Microbiology 152:3091-102|
|Zhao, Xinyan; Zhang, Manxin; Li, Zhongxia et al. (2006) Vaginal protection and immunity after oral immunization of mice with a novel vaccine strain of Listeria monocytogenes expressing human immunodeficiency virus type 1 gag. J Virol 80:8880-90|
|Zhao, Xinyan; Li, Zhongxia; Gu, Baiyan et al. (2005) Pathogenicity and immunogenicity of a vaccine strain of Listeria monocytogenes that relies on a suicide plasmid to supply an essential gene product. Infect Immun 73:5789-98|
|Li, Zhongxia; Zhao, Xinyan; Higgins, Darren E et al. (2005) Conditional lethality yields a new vaccine strain of Listeria monocytogenes for the induction of cell-mediated immunity. Infect Immun 73:5065-73|
|Rayevskaya, Marina; Kushnir, Natasha; Frankel, Fred R (2003) Anti-human immunodeficiency virus-gag CD8+ memory T cells generated in vitro from Listeria-immunized mice. Immunology 109:450-60|
|Rayevskaya, Marina; Kushnir, Natasha; Frankel, Fred R (2002) Safety and immunogenicity in neonatal mice of a hyperattenuated Listeria vaccine directed against human immunodeficiency virus. J Virol 76:918-22|
|Rayevskaya, M V; Frankel, F R (2001) Systemic immunity and mucosal immunity are induced against human immunodeficiency virus Gag protein in mice by a new hyperattenuated strain of Listeria monocytogenes. J Virol 75:2786-91|
|Friedman, R S; Frankel, F R; Xu, Z et al. (2000) Induction of human immunodeficiency virus (HIV)-specific CD8 T-cell responses by Listeria monocytogenes and a hyperattenuated Listeria strain engineered to express HIV antigens. J Virol 74:9987-93|