Physical Resources Core

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ABSTRACT_Core 1 Fc receptors (FcRs) are cell surface proteins that interact with antibody Fc domains to mediate effector cell responses that contribute to the antiviral functionality of antibodies. The diversity of antibodies (isotypes, subclasses, allotypes) and FcRs (types, gene polymorphisms, isoforms) influences antiviral antibody effector functions by modulating the interactions between antigen–antibody immune complexes and FcRs. However, the relative combined contributions of these key variables to protective outcomes in human and rhesus macaque (RM) active and passive immunization studies are unknown. Thus, there is a critical need to characterize how different antibody isotypes, subclasses, allotypes, and FcR alleles impact species-specific FcR-dependent antibody effector functions in order to understand how immunoprophylaxis trials conducted in the RM model can predict outcomes in humans. The overall goal of the Physical Resources Core is to develop and provide this Program with the tools, reagents, samples, and nucleic acid sequence datasets and analyses needed for translation of FcR and antibody Fc genetic diversity among humans and RM to phenotypes, effector functions, and study outcomes. To achieve this, the Physical Resources Core brings together an innovative team of investigators with extensive experience and expertise in the generation, validation, and analysis of next-generation sequencing data; and in the development, production, validation, distribution, and application of novel immunology reagents and materials that are not commercially available. Guided by strong preliminary data, and using a combination of gold-standard and state-of-the art approaches, the Physical Resources Core will achieve the objective of supporting Research Projects 1, 2, 3 and the Overall Program through focus on completion of three Specific Aims: Aim 1. Quantify human FcR diversity in HIV-1 clinical trial participants. Aim 2. Define antibody Fc allotype diversity in humans and RM. Aim 3. Provide immunology reagents and services. Fulfillment of the aims of the Core will be significant and impactful because it will lead to identification of the combinations of nAb and nnAb and effector cell biology for improved understanding of in situ functions. This will provide a roadmap to improve testing accuracy and evaluations of both future active, and immunoprophylaxis, vaccine candidates in human clinical trials. The Physical Resources Core will help generate knowledge essential to accomplishing the Overall Goal of this Program: to determine the impact of antibody allotype and FcR genotype on antiviral outcomes in vitro and in vivo, 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 broad-neutralizing antibody-based prophylactic and therapeutic approaches.