This HIVRAD program builds upon our recent successes in generating stable, proteolytically mature gp140 trimers (SOSIP gp140s) that mimic virion-associated envelope (Env) in topology and antigenicity. The overall goals of this HIVRAD program are reflected in three major milestones: 1) determine the structure of cleaved Env trimers at <4A resolution, 2) demonstrate methods to overcome HIV-1 Env's immunosuppressive properties, and 3) identify a SOSIP trimer vaccine that elicits heterologous neutralization of diverse HIV-1 isolates. These goals are reliant on the preparative production of novel SOSIP trimers in highly purified, homogeneous form. SOSIP trimers are exceptionally complex biomolecules whose production requires a high level of technical expertise, and Core B lends this expertise to the HIVRAD in order to support the goals of Project 1 (HIV-1 Env Vaccine Design, Dr. Moore) and Project 2 (HIV-1 Env Trimer Crystallography, Dr. Wilson). The overall role of Core B is expressed in terms of four Specific Aims: 1) Produce and characterize Env proteins for crystallography studies;2) Produce and characterize Env proteins for immunogenicity studies;3) Evaluate the immunogenicity of Env proteins in small animals, 4) Evaluate Env proteins for effects on human dendritic cells and antigen presentation in vitro. In addition to producing SOSIP trimers, Core B provides a central resource for additional high-quality materials (e.g., gp120 monomers, control antigen, CD4-based proteins, antibody Fabs) that are required by Project 1 and Project 2. Core B also possesses significant experience in vaccine testing and thus will be responsible for performing small-animal immunogenicity studies in collaboration with Project 1. Lastly, Core B will collaborate with external groups to explore and understand the interactions of HIV-1 Env with human dendritic cells in vitro. In addition, Core B will serve as a central point of contact and will manage consortial/contractual agreements with several leading academic and corporate collaborators who lend specialized expertise in the areas of vaccine delivery (Aldevron, Fargo, ND), NAb analyses (Monogram Biosciences, South San Francisco, CA), NAb specificity analyses (Dr. James Binley, Torrey Pines Institute for Molecular Studies, San Diego, CA), in vitro immunogenicity studies (VaxDesign, Orlando, FL), and exploratory immunogenetics (Dr. Sunil Ahuja, University of Texas). In fulfilling these roles, Core B represents an integral element of this innovative, multidisciplinary HIVRAD program.
Nearly 1% of the world's population is infected with HIV, and a preventive vaccine is urgently needed. Most efficacious vaccines elicit antibodies that can neutralize the pathogen, but current-generation HIV vaccines are not effective in this regard. Obstacles include our limited understanding of the structure and immunology of HIV-1 envelope trimers. This HIVRAD represents an innovative approach to addressing these challenges in order to provide a fundamental advance in our ability to elicit HIV-neutralizing antibodies with a vaccine.
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