The need for an effective vaccine against HlV-1 is as urgent as ever. It is currently widely accepted that for a vaccine against HIV to be effective, it should elicit broad and potent anti-HIV neutralizing antibody responses. Anti-HIV neutralizing antibodies (NAbs) target the HIV envelope glycoprotein (Env) on the surface of infectious virions. Despite recent advances in the design of HIV Env-based immunogens, such immunogens have not yet elicited broadly cross-reactive NAbs against primary HIV viruses. The primary reason for this, is that conserved neutralization epitopes, which are present and exposed on such immunogens, are not immunogenic in the context of vaccination. Improving the immunogenicity of such epitopes is crucial for the elicitation of broad anti-HIV neutralizing antibody responses. We currently lack fundamental knowledge on the way B cells recognize such conserved neutralization epitopes on our immunogens and how they subsequently respond to that recognition. In this Project Three, we will investigate how the binding affinity and the duration of the immunogen-BCR interaction, influences the ensuing intracellular events that lead to antibody production. Our plan is to take a 'step back'and examine in detail the interaction between immunogens that express a single HIV neutralization epitope and B cells that express the BCR of that epitope. We will focus our efforts on the epitope recognized by the broadly neutralizing antibody b12. We will determine how the biophysical properties of this interaction define the nature of the ensuing intracellular signaling events that lead to b12-specific B cell antibody responses. These in vitro studies will be complemented by in vivo studies in rhesus macaques (Core B), during which the fate of b12 BCR-expressing B cells will be monitored in the context of immunization and infection. These macaque studies will inform on the evolution of the b12 B cell responses in the contexts of a temporal presentation of immunogen (immunization) and during chronic presentation of the immunogen (SHIV-infection) and on how b12 antibody affinity maturation influences viral-evolution and vice versa.
Our present efforts are highly significant to the eventual development of an effective vaccine against HlV-1, because they aim at understanding the immunological reasons for the lack of immunogenicity of such epitopes on candidate vaccines.
|Zhou, Tongqing; Doria-Rose, Nicole A; Cheng, Cheng et al. (2017) Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation. Cell Rep 19:719-732|
|Jardine, Joseph G; Kulp, Daniel W; Havenar-Daughton, Colin et al. (2016) HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science 351:1458-63|
|McGuire, Andrew T; Gray, Matthew D; Dosenovic, Pia et al. (2016) Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nat Commun 7:10618|
|Strong, Roland K; Finton, Kathryn A K (2016) The Broadly Neutralizing, Anti-HIV Antibody 4E10: an Open and Shut Case? J Virol 90:3274-5|
|Tian, Ming; Cheng, Cheng; Chen, Xuejun et al. (2016) Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires. Cell 166:1471-1484.e18|
|Sok, Devin; Briney, Bryan; Jardine, Joseph G et al. (2016) Priming HIV-1 broadly neutralizing antibody precursors in human Ig loci transgenic mice. Science 353:1557-1560|
|Dosenovic, Pia; von Boehmer, Lotta; Escolano, Amelia et al. (2015) Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice. Cell 161:1505-15|
|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|
|Zhou, Tongqing; Lynch, Rebecca M; Chen, Lei et al. (2015) Structural Repertoire of HIV-1-Neutralizing Antibodies Targeting the CD4 Supersite in 14 Donors. Cell 161:1280-92|
|McGuire, Andrew T; Glenn, Jolene A; Lippy, Adriana et al. (2014) Diverse recombinant HIV-1 Envs fail to activate B cells expressing the germline B cell receptors of the broadly neutralizing anti-HIV-1 antibodies PG9 and 447-52D. J Virol 88:2645-57|
Showing the most recent 10 out of 20 publications