Modulating Ab response to HIV Env gp120 by monoclonal antibody - Resubmission- 1

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

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Abstract

? DESCRIPTION (provided by applicant): A prophylactic vaccine is much needed to control the HIV/AIDS pandemics. One major challenge in the development of an HIV vaccine is induction of potent neutralizing antibodies effective against a large array of HIV-1 isolates. Although a number of monoclonal antibodies have been isolated that neutralize against a vast majority of HIV-1 isolates tested, it remains unclear how these antibodies can be induced by a vaccine. Notably, these antibodies target key conserved epitopes on HIV envelope (Env) and display extensive somatic mutations and/or long CDR H3 in their variable regions. However, factors contributing to generation of such highly mutated antibodies are not understood. This application aims to test a novel idea that induction of Ab response to HIV Env is influenced by a pre-existing anti-Env antibody present during vaccination with Env. Specifically, we hypothesize that administration of a select anti-Env monoclonal antibody at the time of immunization will shape the resultant antibody response in terms of their rate of induction, epitope specificity, and maturation. Earlier studies have shown the use of monoclonal antibodies to direct vaccine-induced endogenous antibody response toward or away from certain epitopes. Indeed, our studies demonstrate that immunization with HIV Env in the presence of a monoclonal anti-CD4-binding site antibody induced high- affinity antibody responses skewed toward neutralizing V3 epitopes. Nonetheless, no studies have examined how monoclonal antibodies direct antibody response toward other more potent and broadly reactive epitopes of HIV Env. It is also unknown if monoclonal antibodies affect the repertoires of antibodies and Ig genes. This application will investigate the potential of monoclonal antibodies to influence the induction of antibodies to the V1V2 region, including epitopes recognized by the potent and broadly neutralizing mAb PG9 and related mAbs such as PG16, CH01, CH04, and 2909. We will administer one or more selected gp120-specific monoclonal antibodies at the time of HIV Env gp120 immunization and evaluate the kinetics, titer, and epitope specificity of endogenous antibody response(s) generated in response to gp120 and the V1V2 region in particular (Aim 1). We will also analyze the effects of monoclonal antibodies on binding affinity and maturation of the gp120 vaccine-induced antibodies (Aim 2). At the completion of this study, we will better understand the role of pre- existing anti-Env antibodies in controlling the repertoire and maturation of the ensuing antibody response generated against HIV Env. The data may inform the development of new strategies for driving the development of high-affinity functional Abs effective against a large array of HIV-1 isolates.