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.
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.
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|Dosenovic, Pia; Kara, Ervin E; Pettersson, Anna-Klara et al. (2018) Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity. Proc Natl Acad Sci U S A 115:4743-4748|
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|Borst, Andrew J; Weidle, Connor E; Gray, Matthew D et al. (2018) Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core. Elife 7:|
|Stamatatos, Leonidas; Pancera, Marie; McGuire, Andrew T (2017) Germline-targeting immunogens. Immunol Rev 275:203-216|
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|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|
|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|
|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|
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