SBIR-STTR Award

Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with naturally occurring viral envelope (Env) proteins. However, it is clear that Env contains epitopes that can induce broadly neutralizing antibodies. Efforts are now focused on ways to modify the HIV-1 Env to improve its ability to induce neutralizing antibodies. The HIV-1 Env is a transmembrane glycoprotein. The membrane-proximal external region of gp41 contains neutralizing epitopes that appear to interact with membrane lipids. These epitopes are the target of three monoclonal antibodies (called 2F5, 4E10, and Z13) that have been isolated from infected patients. These antibodies possess broad cross-neutralization activity against HIV-1 and appear to function by interaction with the peptide epitope and membrane lipids. It is therefore important to consider these membrane interactions in the design of immunogens for vaccines to HIV-1. One experimental approach to this problem is to position the epitopes in proximity to the membrane of a virus-like lipoprotein particle (VLP). Based on the literature describing the use of the hepatitis B surface antigen (HBsAg) as a VLP and immunogen, we hypothesize that it will serve as a suitable carrier molecule for the broadly neutralizing epitopes found in the membrane-proximal external region of the HIV-1 Env protein. In this Phase I SBIR proposal, we propose to create several variants of the HIV-derived epitope sequences fused to the HBsAg VLP moiety so that the most effective immunogens can be identified. The only way to evaluate the immunogenicity of a protein is by immunization, carried out initially in small animal models followed by clinical trials. The Specific Aims of the present Phase I proposal are as follows. - Specific Aim #1: Insert HIV-1 Env gp41 epitopes into the HBsAg. - Specific Aim #2: Evaluate secretion and antigenicity of chimeric HIV-HBsAg particles. - Specific Aim #3: Evaluate immunogenicity of chimeric HIV-HBsAg particles

Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with naturally occurring viral envelope (Env) proteins. However, it is clear that Env contains epitopes that can induce broadly neutralizing antibodies. Efforts are now focused on ways to modify the HIV-1 Env to improve its ability to induce neutralizing antibodies. The HIV-1 Env is a transmembrane glycoprotein. The membrane-proximal external region of gp41 contains neutralizing epitopes that appear to interact with membrane lipids. These epitopes are the target of three monoclonal antibodies (called 2F5, 4E10, and Z13) that have been isolated from infected patients. These antibodies possess broad cross-neutralization activity against HIV-1 and appear to function by interaction with the peptide epitope and membrane lipids. It is therefore important to consider these membrane interactions in the design of immunogens for vaccines to HIV-1. One experimental approach to this problem is to position the epitopes in proximity to the membrane of a virus-like lipoprotein particle (VLP). Based on the literature describing the use of the hepatitis B surface antigen (HBsAg) as a VLP and immunogen, we hypothesize that it will serve as a suitable carrier molecule for the broadly neutralizing epitopes found in the membrane-proximal external region of the HIV-1 Env protein. In this Phase I SBIR proposal, we propose to create several variants of the HIV-derived epitope sequences fused to the HBsAg VLP moiety so that the most effective immunogens can be identified. The only way to evaluate the immunogenicity of a protein is by immunization, carried out initially in small animal models followed by clinical trials. The Specific Aims of the present Phase I proposal are as follows. - Specific Aim #1: Insert HIV-1 Env gp41 epitopes into the HBsAg. - Specific Aim #2: Evaluate secretion and antigenicity of chimeric HIV-HBsAg particles. - Specific Aim #3: Evaluate immunogenicity of chimeric HIV-HBsAg particles.

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