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.

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 #
1P01AI100148-01A1
Application #
8517324
Study Section
Special Emphasis Panel (ZAI1-RRS-A (J1))
Project Start
Project End
Budget Start
2013-02-10
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$585,723
Indirect Cost
$107,733
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Scheid, Johannes F; Horwitz, Joshua A; Bar-On, Yotam et al. (2016) HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535:556-60
Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos et al. (2016) Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352:1001-4
Escolano, Amelia; Steichen, Jon M; Dosenovic, Pia et al. (2016) Sequential Immunization Elicits Broadly Neutralizing Anti-HIV-1 Antibodies in Ig Knockin Mice. Cell 166:1445-1458.e12
McGuire, Andrew T; Gray, Matthew D; Dosenovic, Pia et al. (2016) Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nat Commun 7:10618
Gautam, Rajeev; Nishimura, Yoshiaki; Pegu, Amarendra et al. (2016) A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533:105-9
Zolla-Pazner, Susan; Cohen, Sandra Sharpe; Boyd, David et al. (2016) Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity. J Virol 90:636-49
Halper-Stromberg, Ariel; Nussenzweig, Michel C (2016) Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest 126:415-23
Steichen, Jon M; Kulp, Daniel W; Tokatlian, Talar et al. (2016) HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies. Immunity 45:483-96
Gristick, Harry B; von Boehmer, Lotta; West Jr, Anthony P et al. (2016) Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site. Nat Struct Mol Biol 23:906-915
Scharf, Louise; West, Anthony P; Sievers, Stuart A et al. (2016) Structural basis for germline antibody recognition of HIV-1 immunogens. Elife 5:

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