Recent studies have highlighted the significance of Fc-FcR interactions to achieve in vivo protection for neutralizing antibodies to HIV and other viruses or bacterial toxins through mechanisms including ADCC and ADCVl. We have defined both the amino acid and glycan requirements for IgG Fc binding to FcyRs and developed animal models based on novel strains of FcyR humanized mice to determine the impact of amino acid and glycan modifications of human IgGs on their in vivo function. Despite the growing appreciation for the importance of Fc mediated effector functions to the in vivo potency of antibody mediated viral neutralization for bNAbs to HIV, no systematic studies have been performed to determine the optimal Fc structure that will result in these activities. We will characterize the contributions of Fc structure and effector functions to the activities of the bNAbs isolated by Nussenzweig and generate modified bNAbs optimized for Fc effector functions. These re-engineered bNAbs will be tested in vitro for neutralization, ADCC and ADCVBI and, in collaboration with Nussenzweig, in a novel in vivo neutralization assay, based on the TZM-bl assay in mice that carry human FcyR. In collaboration with Bjorkman we will obtain structural information for these modified antibody Fc's, alone and in complex to specific FcyRs, These data will direct the generation of additional variants to further enhance Fc-FcyR function. These studies will result in the generation of novel, bNAbs optimized for both neutralization and effector function and provide the framework to develop immunization strategies that will result in bNAbs with optimal effector properties.
The generation of effective anti-HIV immunity remains a formidable challenge to global health. Through the studies proposed in this subproject we will investigate mechanisms to enhance immunogenicity of potential target antigens to generate neutralizing antibodies and to engineer neutralizing antibodies to augment their in vivo activity.
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|Halper-Stromberg, Ariel; Lu, Ching-Lan; Klein, Florian et al. (2014) Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158:989-99|
|Bournazos, Stylianos; Klein, Florian; Pietzsch, John et al. (2014) Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158:1243-53|
|Ahmed, Alysia A; Giddens, John; Pincetic, Andrew et al. (2014) Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. J Mol Biol 426:3166-79|
|Scharf, Louise; Scheid, Johannes F; Lee, Jeong Hyun et al. (2014) Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell Rep 7:785-95|
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|Shingai, Masashi; Nishimura, Yoshiaki; Klein, Florian et al. (2013) Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503:277-80|
|Horwitz, Joshua A; Halper-Stromberg, Ariel; Mouquet, Hugo et al. (2013) HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A 110:16538-43|
|Chuang, Gwo-Yu; Acharya, Priyamvada; Schmidt, Stephen D et al. (2013) Residue-level prediction of HIV-1 antibody epitopes based on neutralization of diverse viral strains. J Virol 87:10047-58|
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