For the past three decades intense efforts by numerous investigators aimed at the design of immunogens that would stimulate the production of broadly neutralizing antibodies (bnAbs). Although improvements were made in the design/engineering, expression and purification of Env-based, in general the neutralizing antibody responses elicited by such immunogens are narrow in breadth and potency. One of the known targets of bnAbs is the CD4-BS of the HIV Env. Regarding the inability of recombinant Envs to elicit anti- CD4-BS, our studies suggest that one reason for this is that Env immunogens do not engage the germline forms of known anti-CD4-BS bnAbs and of the corresponding germline B cell receptors (BCRs). We believe that a direct consequence of this lack of Env-BCR reactivity is that the process of production of such antibodies is not initiated by such Env immunogens. Our proposed studies are based on our recent design of a trimeric gp140 clade C Env protein that engages the germline VRCOI and NIH45-46 antibodies (two of the most potent and broadly neutralizing anti-CD4-BS antibodies known) and activate B cells that express the corresponding BCR forms of these antibodies. We believe, therefore, that we identified a way to overcome the earliest roadblock in the elicitation of such bNAbs. As such, our findings are very novel and highly significant to efforts to develop by immunization bNAbs against HIV. In this Project One, we propose to further optimize our immunogens to improve their ability to engage and activate the germline BCRs of known anti-CD4-BS bNAbs. This Project One has three Specific Aims: 1) Optimize the design of our current immunogens to expand their germline BCR-activation capabilities;2) Engineer and characterize a modified variant of our immunogen that lacks specific variable domains, and 3) Design/optimize immunogens for macaque BCR activation. The proposed research in Project One is central to the overall activities and aims of our IPCAVD Program.

Public Health Relevance

Our proposed studies aimed to overcome an early block in the elicitation of broadly neutralizing antibodies against HIV. Broadly neutralizing antibodies will be a critical component of an effective AIDS vaccine. As such our studies are highly significant in the development of a vaccine against this devastating disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-NVM-A (S1))
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Seattle Biomedical Research Institute
United States
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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
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
Yacoob, Christina; Pancera, Marie; Vigdorovich, Vladimir et al. (2016) Differences in Allelic Frequency and CDRH3 Region Limit the Engagement of HIV Env Immunogens by Putative VRC01 Neutralizing Antibody Precursors. Cell Rep 17:1560-1570
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; 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