A subset of humans infected with HIV-1 develops broadly neutralizing antibody responses to multiple epitopes on the envelope glycoproteins (Env), including the CD4-binding site (CD4bs) and VI/V2 region. However, immunization with Env-based vaccine candidates has yet to elicit such effective responses for reasons that are not yet fully understood. To help understand and bypass this roadblock, we have developed new bioinformatics methods for analysis of B cell deep sequencing data to provide a high-resolution view of the "antibodyome" and its response to antigenic stimuli. These new tools provide an opportunity for significant advances in understanding the humoral immune response to HIV-1 Env immunogens. The goals of our Project are in two distinct areas. First, we will analyze deep sequencing data of B cell transcripts, obtained from the NHP immunization experiments described in detail in Projects 1 and 2 (and performed in Core B) to characterize the antibody populations that arise in response to immunization and their development pathways. Our second focus will be to use x-ray crystallography to determine atomic-level structures of high-interest antibodies we identify, and their relevant antibody/antigen complexes. All of these analytical efforts will be evaluated and synthesized with data from Projects 2 and 3 to directly feedback to Project 1 to inform Env immunogen redesign to impact elicited B cell responses in the second round of planned NHP experiments in Year 4 of this proposal.
Our Specific Aims are as follows: (1) To use deep sequencing of memory B cell transcripts to identify and genetically characterize NHP antibodies elicited by soluble Env trimers. These studies will identify the the V, D, and J gene segments used, and otherwise characterize the antibody response. In the second round of NHP experiments, we will use new immunogens optimized by molecular design or in vitro evolution, described in Project 1. (2) We will define the maturation pathways for select identified antibodies;and (3) We will determine structures of elicited antibodies of high interest, and relevant antibody/antigen complexes.
Some individuals develop broadly neutralizing humoral immune responses to HIV-1 infection, but candidate vaccines have not yet been able to elicit such effective responses. We describe new methods to enable observation of antibody development at high resolution. We will apply these methods to help understand the immune response to vaccination in non-human primates to potentially bypass this roadblock.
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|Guenaga, Javier; Dubrovskaya, Viktoriya; de Val, Natalia et al. (2016) Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers. J Virol 90:2806-17|
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|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|
|Ingale, Jidnyasa; Stano, Armando; Guenaga, Javier et al. (2016) High-Density Array of Well-Ordered HIV-1 Spikes on Synthetic Liposomal Nanoparticles Efficiently Activate B Cells. Cell Rep 15:1986-99|
|Chen, Yajing; Wilson, Richard; O'Dell, Sijy et al. (2016) An HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes. J Immunol 197:3982-3998|
|Wang, Yimeng; Sundling, Christopher; Wilson, Richard et al. (2016) High-Resolution Longitudinal Study of HIV-1 Env Vaccine-Elicited B Cell Responses to the Virus Primary Receptor Binding Site Reveals Affinity Maturation and Clonal Persistence. J Immunol 196:3729-43|
|Schramm, Chaim A; Sheng, Zizhang; Zhang, Zhenhai et al. (2016) SONAR: A High-Throughput Pipeline for Inferring Antibody Ontogenies from Longitudinal Sequencing of B Cell Transcripts. Front Immunol 7:372|
|Dai, Kaifan; Khan, Salar N; Wang, Yimeng et al. (2016) HIV-1 Vaccine-elicited Antibodies Reverted to Their Inferred Naive Germline Reveal Associations between Binding Affinity and in vivo Activation. Sci Rep 6:20987|
|Phad, Ganesh E; VÃ¡zquez Bernat, NÃ©stor; Feng, Yu et al. (2015) Diverse antibody genetic and recognition properties revealed following HIV-1 envelope glycoprotein immunization. J Immunol 194:5903-14|
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