So far, generation of broadly neutralizing antibody responses against diverse primary HIV isolates has beenan elusive target. Therefore, the aim of this project is to design and evaluate novel Env immunogens for theirability to induce broadly neutralizing antibody responses against diverse primary isolates. We previouslyreported that an Env immunogen (o-gp140SF162DV2) containing a partial deletion in the second variableloop (V2) derived from SF162 (R5 tropic), when used in a DMA prime-protein boost regimen in rhesusmacaques, induced neutralizing antibodies against some heterologous subtype B primary isolates as well asprotection to the vaccinated animals upon challenge with pathogenic SHIVSF162P4. We plan to continueworking on trimeric Env and use four complementary approaches to further enhance the exposure ofconserved neutralizing epitopes to improve the efficacy of Env immunogens in inducing broadly neutralizingantibodies and protection in challenge model. In the first, we propose to increase the exposure of conservedneutralizing epitopes involved in receptor and co-receptor binding regions of the Env by introducing deletionsin V-regions and 'bridging-sheet' following rational and random approaches. In the second, we seek toexpose neutralizing epitopes by introducing site specific or global deglycosylation either alone or incombination with b-sheet and/or V- loops. In the third, we seek to expose these epitopes by the use of Envcomplexed to rationally designed CD4 mimics or other scaffolds. Lastly, we propose to express Env trimer innon-glycosylated form to enhance the exposure of critical neutralizing epitopes that are shielded byextensive glycosylation. We will use subtype B antigens as a model for evaluating the efficacy of variousapproaches mentioned above. The best approach will be used for optimizing Env antigens from othersubtypes e.g. A and C. We will screen candidate immunogens for expression, CD4-binding, and binding to apanel of monoclonal antibodies of known specificities. Once a candidate has met pre-defined criteria, it thenwill be advanced to immunogenicity studies in rabbits. Neutralizing antibody and cellular responses inducedby the lead candidate will be optimized using adjuvants, formulations, and vaccine regimens. The best Envimmunogen will be advanced to vaccine/challenge studies in primates. These studies should yield importantinformation for the design of next generation HIV vaccines for future clinical evaluations.
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