Impact of Antibody Effector Function Diversity on Antiviral Activity In Situ

ABSTRACT_Overall Preventing HIV-1 acquisition and extinguishing virus replication is a key goal for vaccine and immunoprophylaxis strategies. Diverse antibody (Ab) Fc receptor (FcR)-mediated functions and multiple effector cell populations engage in vivo in a joint merger to thwart infection. An improved understanding of specific functional and qualitative features of the humoral response and how they contribute to protective efficacy is needed. Results from immune correlates analyses of vaccine efficacy trials, immunoprophylaxis trials and preclinical studies indicate that antibody constant (Fc) region mediated antiviral activity is an untapped source of antiviral functions to afford broad and potent protection against HIV infection. Full exploitation of this potential demands a more complete understanding of Fc-mediated immune mechanisms in humans and animal models. Rational design of prevention methods requires more information regarding epitope targets, cognate polyclonal antibody (Ab) isotypes and subclasses, diverse FcR and effector cell populations, and most important, how these elements can be pulled together for the greatest antiviral impact. The goal of this program is to define how Fc-mediated immunity can be used for preventing, treating, curing HIV infection. We propose to determine the combined impact of antibody Fc and effector cells on antiviral outcomes in situ, thus informing how antibody Fc effector functions can be used to improve antibody- based vaccine strategies, increase the relative antiviral activity of HIV-1 specific antibody subclasses, and augment bnAb- based prophylactic and therapeutic approaches. Our central hypothesis is that antibody antiviral potency is maximal when multiple antibody specificities and subclasses are combined and that their antiviral functions are modulated by the in vivo localization of FcR-bearing effector cells and host genetic determinants of Fc-FcR engagement. Harnessing Fc function will improve bnAb vaccine strategies given the need to increase the antiviral functions of neutralizing antibodies (nAbs) at sub-efficacious levels. Toward this end, we propose three synergistic, inter-related Projects supported by two Cores and an Administrative Core to achieve the following Overall Aims: 1. Identify combinations of bnAb and nnAb antibody specificities with maximal antiviral activity. 2. Define the contribution of antibody Fc domain (subclass, allotype) on antiviral functions. 3. Determine FcR and effector cell populations responsible for maximal Ab Fc antiviral functions in situ.