An improved understanding of how B cell responses to the HlV-1 envelope glycoproteins (Env) are regulated is needed to accelerate the development of an HIV-1 vaccine. In this project, we will investigate the B cell repertoire engaged in the initial response to Env and determine how this response evolves over time. Our recently established methodology to conduct basic B cell studies in non-human primates (NHPs) represents a substantial step forward for vaccine research and an opportunity to obtain information about B cell maturation and selection processes that will directly impact the design of improved Env immunogens and the selection of Env immunogens for use in clinical trials.
In Aim 1, we will use existing NHP samples from Env trimer immunized macaques to examine if a longer immunization interval stimulates antibodies that display an incresaed level of somatic hypermutation (SHM). We will also examine genetic features ofthe memory B cell repertoire directed against the CD4-binding site (CD4bs) of Env and ask if critical B cell specificities are lost as the response evolves over time.
In Aim 2, we will examine B cell responses elicited by new generation soluble Env trimers and isolate monoclonal antibodies for genetic and functional analysis. Specifically, we will ask if the V(D)J gene usage ofthe CD4bs-specific B cell repertoire is altered when immunogens engineered to present the CD4bs in a conformation-constrained manner are used, or in response to sequential prime-boosting with heterologous immunogens, and we will assess the impact of this on the antibody neutralizing activity.
In Aim 3, we will investigate the Env-specific repertoire of long-lived plasma cells residing in the bone marrow of immunized rhesus macaques.
This aim will include the development of methods to optimize single cell sorting of bone marrow-resident plasma cells. We will ask if the bone marrow repertoire is established early in the immune response and how diverse this population is compared to the Env-specific memory B cell pool. By addressing these questions, we hope to obtain an improved understanding about Env immunogenicity in healthy, primate hosts that is of direct relevance for the design of improved HIV-1 immunogens and the selection of Env candidates for clinical studies.
The major objective of Project 2 is to investigate features of vaccine-induced B cell responses against HlV-1 Env to more successfully design vaccine regimens that elicit broadly neutralizing antibodies. The successful elicitation of such antibodies would be a large step forward toward the goal of generating a broadly effective HIV-1 vaccine and would have a substantial impact on improving human public health.
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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|
|Bonsignori, Mattia; Zhou, Tongqing; Sheng, Zizhang et al. (2016) Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. Cell 165:449-63|
|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|
|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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