Effective AIDS vaccines will likely need to elicit antibodies that can neutralize diverse strains of HIV, but vaccine immunogens based on soluble HIV Env constructs have, so far, failed to elicit such responses. Our first-generation attempts to design 'epitope-scaffold'antigens for bNAb 4E10 generate exquisite epitope-specific responses that, unfortunately, also fail to potently neutralize HIV. In order to improve on this approach (and embrace parallel strategies), we will now focus on the broadly neutralizing, CD4-binding site antibody b12. We propose to iteratively engineer b12-specific i) epitope-scaffolds and ii) minimized gp120 constructs, with binding optimized to both mature b12 and its germline precursor;the latter recognition event is essential for selectively activating the correct naive B cells that will lead to b12-equivalent responses. The biophysical parameters describing BCR/antigen interactions (affinities, kinetics, thermodynamics) have been shown to have profound effects on the course of humoral immune responses. We will test the hypothesis that i) b12 germline candidates will not completely recapitulate the binding, structural or neutralization properties of the mature antibody by some subset of the parameters that describe protein/protein interactions and function and ii) that, in order for designed immunogens to induce effective b12-like responses upon immunization, both immunogen/b12 and immunogen/germline interactions will need to be recapitulated. Since no single b12 germline precursor can confidently be identified, we propose to study the structures (using x-ray crystallography and small-angle x-ray scattering (SAXS)) and binding properties (using SPR and ITC) of an ensemble of the 12 likeliest candidates. Our proposed comprehensive biophysical studies of mature b12 and the complete ensemble of candidate b12 germline precursor antibodies will: i) support the rational immunogen redesign cycle in Project 1;ii) detail the molecular mechanisms of b12 maturation;and iii) provide the biophysical framework for interpreting the in vitro and in vivo B cell activation assays in Project 3. Our research goal is to understand the biophysical constraint/s on B cell activation thresholds for an epitope of one of the most potent and broadly anti-HlV-1 neutralizing MAbs known. We will then use these results to guide efforts to rationally design better immunogens to elicit anti-HIV NAbs while contributing significantly to the field of fundamental B cell immunology, combining basic and applied research goals.
No effective AIDS vaccine strategy has been developed, despite promising leads;such will be needed to complement multi-drug, highly-active anti-retroviral therapy (HAART), which only delays progression with limited prophylactic applications, and in the developing world, where access to HAART is limited. We propose applying a second-generation version (targeting mature and germline responses) of a novel vaccine immunogen development strategy ('epitope-scaffolding') and rational minimization of HIV gpl 20 to effectively recapitulate known broadly-neutralizing antibody responses (b12) in vaccinees to prevent HIV infection.
|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|
|Jardine, Joseph G; Kulp, Daniel W; Havenar-Daughton, Colin et al. (2016) HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science 351:1458-63|
|Tian, Ming; Cheng, Cheng; Chen, Xuejun et al. (2016) Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires. Cell 166:1471-1484.e18|
|Strong, Roland K; Finton, Kathryn A K (2016) The Broadly Neutralizing, Anti-HIV Antibody 4E10: an Open and Shut Case? J Virol 90:3274-5|
|Jardine, Joseph G; Ota, Takayuki; Sok, Devin et al. (2015) HIV-1 VACCINES. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science 349:156-61|
|Zhou, Tongqing; Lynch, Rebecca M; Chen, Lei et al. (2015) Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors. Cell 161:1280-92|
|Dosenovic, Pia; von Boehmer, Lotta; Escolano, Amelia et al. (2015) Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice. Cell 161:1505-15|
|McGuire, Andrew T; Glenn, Jolene A; Lippy, Adriana et al. (2014) Diverse recombinant HIV-1 Envs fail to activate B cells expressing the germline B cell receptors of the broadly neutralizing anti-HIV-1 antibodies PG9 and 447-52D. J Virol 88:2645-57|
|McGuire, Andrew T; Dreyer, Anita M; Carbonetti, Sara et al. (2014) HIV antibodies. Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies. Science 346:1380-3|
|Finton, Kathryn A K; Friend, Della; Jaffe, James et al. (2014) Ontogeny of recognition specificity and functionality for the broadly neutralizing anti-HIV antibody 4E10. PLoS Pathog 10:e1004403|
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