In the B Cell Focus our overall goals are to 1) design Env immunogens that will elicit both difficult-to-induce broad neutralizing antibodies, and also 2) induce easier-to-induce protective antibodies. The goal is to induce both types of antibodies in most vaccinated subjects.
Specific aims i nclude:
Aim 1. To define the nature of protective systemic and mucosal immunity in vaccinated subjects.
Aim 2. To design novel gp120/gp140 immunogens that induces protective mucosal and systemic antibody responses to HlV-1.
Aim 3. To define host factors that may limit the induction of broadly neutralizing antibodies.
Aim 4. To design immunogens that target unmutated ancestor and intermediate antibodies of the maturation pathways of protective anti-HlV-1 Env antibodies.
Aim 5. To use structural biological information and technology to design immunogens. Thus, the B Cell Focus will use recombinant monoclonal antibody technology to study unique mucosal samples from those vaccinated with current vaccines;will work to define the types of antibodies and their protective nature induced at mucosal sites (Aim 1);will test new, more antigenic and immunogenic transmitted/founder Env immunogens in Aim 2, will determine tolerance and other immunoregulatory host factors that control induction of difficult-to-induce broadly neutralizing antibodies (BnAbs) (Aim 3);will isolate clonal lineages of BnAbs to define precursor antibodies to use as templates upon which to design new immunogens for driving unusual or complex maturation pathways (Aim 4), and will solve the near atomic resolution structure of the membrane associated trimer by cryoEM for rationale vaccine design (Aim 5). The work of the B Cell Focus builds on discoveries made over the past 6 years in CHAVI, and aims to overcome the current roadblocks preventing inducing protective antibodies in the majority of vaccinated subjects.

Public Health Relevance

Characterization of the antibody specificities in the settings of vaccination and those rare infected people who make desired antibody responses will allow a better understanding of the easy vs. harder to induce protective antibodies and will aid in the design of immunogens that induce antibody responses that effectively prevent HIV transmission regardless of the portal of entry.

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 #
5UM1AI100645-02
Application #
8508867
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$13,822,107
Indirect Cost
$3,365,586
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Castillo-Menendez, Luis R; Witt, Kristen; Espy, Nicole et al. (2018) Comparison of Uncleaved and Mature Human Immunodeficiency Virus Membrane Envelope Glycoprotein Trimers. J Virol 92:
Brown, Eric P; Weiner, Joshua A; Lin, Shu et al. (2018) Optimization and qualification of an Fc Array assay for assessments of antibodies against HIV-1/SIV. J Immunol Methods 455:24-33
Finney, Joel; Yeh, Chen-Hao; Kelsoe, Garnett et al. (2018) Germinal center responses to complex antigens. Immunol Rev 284:42-50
Pardi, Norbert; Hogan, Michael J; Naradikian, Martin S et al. (2018) Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 215:1571-1588
Eudailey, Joshua A; Dennis, Maria L; Parker, Morgan E et al. (2018) Maternal HIV-1 Env Vaccination for Systemic and Breast Milk Immunity To Prevent Oral SHIV Acquisition in Infant Macaques. mSphere 3:
Kelsoe, Garnett; Haynes, Barton F (2018) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Breaking through Immunity's Glass Ceiling. Cold Spring Harb Perspect Biol 10:
Wagh, Kshitij; Kreider, Edward F; Li, Yingying et al. (2018) Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth. Cell Rep 25:893-908.e7
Fu, Qingshan; Shaik, Md Munan; Cai, Yongfei et al. (2018) Structure of the membrane proximal external region of HIV-1 envelope glycoprotein. Proc Natl Acad Sci U S A 115:E8892-E8899
Fera, Daniela; Lee, Matthew S; Wiehe, Kevin et al. (2018) HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope. Nat Commun 9:1111
McMichael, Andrew J (2018) Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? Could a CD8+ T-Cell Vaccine Prevent Persistent HIV Infection? Cold Spring Harb Perspect Biol 10:

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