Abstract

The B Cell Biology Scientific Research Support Component (SRSC) will assist in the generation of novel vaccines that target broad neutralizing antibodies (BnAbs) or other protective B-cell precursors by B lineage immunogen design. The novel vaccines generated by the CHAVI-ID B Cell Focus will be designed to activate the unmutated ancestors (UA) of highly mutated BnAb B cells isolated by flow cytometry. As a parallel strategy, this B Cell Biology SRSC will first isolate human B-cell precursors, and drives their maturation in vitro. BnAb precursors will then be identified and allowed to proliferate, mature and undergo Ig class-switching (CSR) in vitro. In this manner, the B Cell Biology SRSC will complement the work of the B Lineage Immunogen Design teams by identifying and selecting BnAb precursors -unmutated ancestors B cells - that are comparable to, and possibly better than, those inferred from BnAb clonal lineages. This support component will identify, isolate, characterize, and activate de novo B cells capable of generating BnAb responses, allowing the direct study of BnAb UA and intermediate antibody (IA) B cells.
Specific Aims Aim 1. Culture Env-specific immature B cells from human bone marrow in vitro and drive them to express AID and undergo Ig class-switch recombination in vitro to characterize BnAb maturation pathways.
Aim 2. Culture Env-specific immature B cells from humanized Velocimmune? mice in vitro and drive antigen-specific B cells to compete and mature by AID expression and Ig CSR to characterize BnAb maturation pathways.
Aim 3. Immunize immunoglobulin humanized mice with candidate Env vaccines to determine their immunogenicity by characterizing serum antibody responses and hybridoma lines.

Public Health Relevance

This support component will grow human and immunoglobulin humanized mouse B cells in test tubes and these will be used to identify candidate HlV-1 vaccine antigens. This approach will allow novel molecular vaccine designs to be tested inexpensively, rapidly, and ethically.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
1UM1AI100645-01
Application #
8385839
Study Section
Special Emphasis Panel (ZAI1-JBS-A (M1))
Project Start
Project End
Budget Start
2012-07-15
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$707,727
Indirect Cost
$256,945

  Institution

Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Finney, Joel; Kelsoe, Garnett (2018) Poly- and autoreactivity of HIV-1 bNAbs: implications for vaccine design. Retrovirology 15:53
Bradley, Todd; Peppa, Dimitra; Pedroza-Pacheco, Isabela et al. (2018) RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses. Cell 175:387-399.e17
Richard, Jonathan; Prévost, Jérémie; Baxter, Amy E et al. (2018) Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses. MBio 9:
Pardi, Norbert; Hogan, Michael J; Porter, Frederick W et al. (2018) mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov 17:261-279
Bowder, Dane; Hollingsead, Haley; Durst, Kate et al. (2018) Contribution of the gp120 V3 loop to envelope glycoprotein trimer stability in primate immunodeficiency viruses. Virology 521:158-168
Madani, Navid; Princiotto, Amy M; Mach, Linh et al. (2018) A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Nat Commun 9:2363
Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146
Dong, Yuanchen; Chen, Shuobing; Zhang, Shijian et al. (2018) Folding DNA into a Lipid-Conjugated Nanobarrel for Controlled Reconstitution of Membrane Proteins. Angew Chem Int Ed Engl 57:2072-2076
Prévost, Jérémie; Richard, Jonathan; Medjahed, Halima et al. (2018) Incomplete Downregulation of CD4 Expression Affects HIV-1 Env Conformation and Antibody-Dependent Cellular Cytotoxicity Responses. J Virol 92:
Prévost, Jérémie; Richard, Jonathan; Ding, Shilei et al. (2018) Envelope glycoproteins sampling states 2/3 are susceptible to ADCC by sera from HIV-1-infected individuals. Virology 515:38-45

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