Mechanisms of Antibody Fc Mediated Protection

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ABSTRACT_Project 1 Major efforts to develop HIV vaccines and other immunoprevention approaches are based on the premise that anti-Env antibody (Ab) responses will protect against HIV, SIV or SHIV in humans and nonhuman primates (NHP) if present before exposure. Humoral responses comprise two Ab functions that must be considered for HIV prevention: direct neutralizing activity, enabled by epitope-paratope interactions; and the recruitment of antiviral effector cells (NK cells, monocytes, granulocytes), via Fc-Fc receptor interactions. Although applications of neutralizing activity have been exhaustively studied, the utility of antibody Fc-mediated functions in HIV prevention is only partially defined. Further, how these functions allow non-neutralizing antibodies (nnAbs) to afford protective human immunity is an unresolved but significant question as many nnAbs recognize invariant epitopes, can be raised by vaccination, and recruit Fc-mediated effector functions in experimental settings. It is likely that past limitations in establishing clear links between protection and nnAb FC-mediated functions may be explained by an incomplete understanding of target epitope sensitivity, optimal applications of Abs and/or usage of animal models for efficacy testing. Accordingly, the goal of this project is to fill these information gaps and determine whether and how Fc-mediated immune functions can be most effectively employed for the rational design of HIV prevention methods. We will use recent advances in animal models and Fc-FcR dependent immunity to build new approaches that can bridge epitope presentation patterns, effector cell recruitment and target cell killing in situ, and protective efficacy in vivo. We will validate two hypothetical scenarios for Fc-mediated immunity in preventing HIV infection suggested by our data. 1) Non-neutralizing Abs will exhibit efficacy in a human immune background according to identifiable qualities of epitope targeting, isotype and Fc-mediated effector mechanism. 2) Polyclonal mixtures of bnAbs and cross- reactive nnAbs will afford more potent protection in a human immune background than either Ab type alone; thus affording protective efficacy in vivo at what would otherwise be limiting titers. These will be tested using novel in vitro systems and immunodeficient mice reconstituted to produce human backgrounds and effector mechanisms, as well as comparative experiments in RM immune backgrounds. The Specific Aims are: Aim 1. Identify windows of vulnerability to Fc-mediated activities in a primary infection system. Aim 2. Demonstrate that nnAbs and their Fc-dependent functions, alone and/or with sub-efficacious bnAb titers, protect against HIV infection in vivo.