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HIVRAD MISSION: We seek to develop insights into mechanisms by which antibodies (Abs) protect against HIV infection to facilitate design of improved Abs and effective immunogens. Development of effective vaccines or delivered Abs to control infection will require understanding of Ab interactions with antigen and with Ab receptors that mediate effector functions. Using knowledge of what Env mutations arise in response to HIV infection inhumanized mice allows structural/bioinformatic analyses of which features promote Ab evasion, required information for designing broadly neutralizing antibodies (bNAbs) that are insensitive to common routes of viral evasion. This knowledge will allow optimization of the breadth/potency of bNAbs for passive delivery (both by injection and gene therapy “reverse vaccination”) and is required for effective immunogen design for vaccines, thus our project is relevant to both traditional and “reverse” vaccine strategies to combat HIV. To accomplish these goals and to establish basic principles underlying Ab-mediated protection, we will combine the expertise of the Nussenzweig, Ravetch, and Bjorkman laboratories in characterization of HIV bNAbs and humanized mouse models of HIV infection, antibody effector function evaluation and improvement, and the structural biology of Ab-HIV and Ab-receptor interactions. Our proposal comprises three separate, but inter-related and inter-dependent collaborative projects, with the following aims: (1) Test designed bNAbs ina humanized mouse model of HIV infection, sequence resistant HIV strains, evaluate bNAbs for ability tocontrol established HIV infection in humanized mice, and evaluate novel immunogens in a mouse model;
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