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 Fc?Rs and developed animal models based on novel strains of Fc?R 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 Fc?R. In collaboration with Bjorkman we will obtain structural information for these modified antibody Fc's, alone and in complex to specific Fc?Rs, These data will direct the generation of additional variants to further enhance Fc-Fc?R 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI100148-03
Application #
8786049
Study Section
Special Emphasis Panel (ZAI1-RRS-A)
Project Start
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
3
Fiscal Year
2015
Total Cost
$462,346
Indirect Cost
$90,417
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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Stadtmueller, Beth M; Bridges, Michael D; Dam, Kim-Marie et al. (2018) DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions. Immunity 49:235-246.e4
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Mayer, Christian T; Gazumyan, Anna; Kara, Ervin E et al. (2017) The microanatomic segregation of selection by apoptosis in the germinal center. Science 358:
Wang, Haoqing; Gristick, Harry B; Scharf, Louise et al. (2017) Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies. Elife 6:
Horwitz, Joshua A; Bar-On, Yotam; Lu, Ching-Lan et al. (2017) Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo. Cell 170:637-648.e10
Nishimura, Yoshiaki; Gautam, Rajeev; Chun, Tae-Wook et al. (2017) Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543:559-563

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