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.
|Karlsson Hedestam, Gunilla B; Guenaga, Javier; Corcoran, Martin et al. (2017) Evolution of B cell analysis and Env trimer redesign. Immunol Rev 275:183-202|
|Kwong, Peter D; Chuang, Gwo-Yu; DeKosky, Brandon J et al. (2017) Antibodyomics: bioinformatics technologies for understanding B-cell immunity to HIV-1. Immunol Rev 275:108-128|
|Guenaga, Javier; Garces, Fernando; de Val, Natalia et al. (2017) Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein. Immunity 46:792-803.e3|
|Stano, Armando; Leaman, Daniel P; Kim, Arthur S et al. (2017) Dense Array of Spikes on HIV-1 Virion Particles. J Virol 91:|
|Martinez-Murillo, Paola; Tran, Karen; Guenaga, Javier et al. (2017) Particulate Array of Well-Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach. Immunity 46:804-817.e7|
|Wang, Yimeng; O'Dell, Sijy; Turner, Hannah L et al. (2017) HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates. J Virol 91:|
|Bale, Shridhar; Goebrecht, Geraldine; Stano, Armando et al. (2017) Covalent Linkage of HIV-1 Trimers to Synthetic Liposomes Elicits Improved B Cell and Antibody Responses. J Virol 91:|
|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|
|Longo, Nancy S; Sutton, Matthew S; Shiakolas, Andrea R et al. (2016) Multiple Antibody Lineages in One Donor Target the Glycan-V3 Supersite of the HIV-1 Envelope Glycoprotein and Display a Preference for Quaternary Binding. J Virol 90:10574-10586|
|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|
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