This application aims at improving our understanding of the frequency and characteristics of nave B cells that are the precursors of those that produce VRC01-class broadly neutralizing antibodies (bNAbs). VRC01-class bNAbs bind the CD4-binding site of the HIV Env and are among the most potent and broadly neutralizing antibodies known. They protect animals from experimental infection and when administered passively to chronically-infected patients they reduce plasma viremia. VRC01-like antibodies are therefore the type of antibodies one would want to elicit by vaccination. So far, however, this has not been achieved. We do know quite a few things about the mutated forms of VRC01-class antibodies, but there are many critical gaps in our knowledge of the germline form of these antibodies. Lab-engineered 'predicted' germline forms of such antibodies do not recognize Env. This information has led us and others to hypothesize that recombinant Envs fail to stimulate nave B cells expressing germline VRC01-class B cell receptors (BCRs). However, the true nature of germline VRC01-class antibodies/BCRs is not known, so many of the assumptions we make about their infrequent elicitation during infection and their non-elicitation during immunization may be inaccurate. Here we will employ innovative and complementary methodologies and an interactive experimental approach to define the frequencies of nave human B cells expressing germline VRC01-class BCRs, to define the true germline amino acid sequences of these antibodies/BCRs and to define their Env-recognition properties. The information gathered by our proposed studies will be critical to better understand how HIV-1 interacts with particular nave B cells and also will be important for the design of Env-based immunogens capable of engaging the broadest possible array of germline VRC01-class BCRs.

Public Health Relevance

Our study aims at improving our understanding of the interaction between the HIV-1 Env and nave B cells that are the precursors of those that produce broadly neutralizing HIV-1 antibodies. Our proposed studies aim at filling key gaps in our knowledge on how such antibodies are generated during HIV-1 infection and how they will be elicited by vaccination.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Immunology and Pathogenesis Study Section (AIP)
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Mcdonald, David Joseph
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Fred Hutchinson Cancer Research Center
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Briney, Bryan; Sok, Devin; Jardine, Joseph G et al. (2016) Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies. Cell 166:1459-1470.e11
Yacoob, Christina; Pancera, Marie; Vigdorovich, Vladimir et al. (2016) Differences in Allelic Frequency and CDRH3 Region Limit the Engagement of HIV Env Immunogens by Putative VRC01 Neutralizing Antibody Precursors. Cell Rep 17:1560-1570
Cohen, Kristen W; Dugast, Anne-Sophie; Alter, Galit et al. (2015) HIV-1 single-stranded RNA induces CXCL13 secretion in human monocytes via TLR7 activation and plasmacytoid dendritic cell-derived type I IFN. J Immunol 194:2769-75
Pritchard, Laura K; Spencer, Daniel I R; Royle, Louise et al. (2015) Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies. Nat Commun 6:7479
Jardine, Joseph G; Ota, Takayuki; Sok, Devin et al. (2015) HIV-1 VACCINES. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science 349:156-61
Dugast, Anne-Sophie; Stamatatos, Leonidas; Tonelli, Andrew et al. (2014) Independent evolution of Fc- and Fab-mediated HIV-1-specific antiviral antibody activity following acute infection. Eur J Immunol 44:2925-37
Cohen, Kristen; Altfeld, Marcus; Alter, Galit et al. (2014) Early preservation of CXCR5+ PD-1+ helper T cells and B cell activation predict the breadth of neutralizing antibody responses in chronic HIV-1 infection. J Virol 88:13310-21
Jardine, Joseph; Julien, Jean-Philippe; Menis, Sergey et al. (2013) Rational HIV immunogen design to target specific germline B cell receptors. Science 340:711-6
McGuire, Andrew T; Hoot, Sam; Dreyer, Anita M et al. (2013) Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies. J Exp Med 210:655-63
Diskin, Ron; Klein, Florian; Horwitz, Joshua A et al. (2013) Restricting HIV-1 pathways for escape using rationally designed anti-HIV-1 antibodies. J Exp Med 210:1235-49

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