Our overall goal is to understand the host immune response to vaccination with soluble recombinant HIV-1 Envelope immunogens in non-human primates (NHP), with the aim of developing Envelope-based vaccines that can elicit broadly neutralizing antibodies. 20-30% of HIV-1-infected subjects develop broadly neutralizing antibodies (bNAbs) within the first three years after infection, given sufficient antigenic stimulation from replicating virus and proper CD4+ T cell help. Even in an environment of HIV-related immune dysregulation, this subset of subjects is able to successfully produce bNAbs, providing hope that this can be accomplished by vaccination in healthy subjects. Currently it is not understood why Env-based vaccines have failed to elicit bNAbs in both NHP and humans, despite displaying the conserved epitopes of some of the most broadly neutralizing anti-HIV-1 antibodies known. It is possible that B Cell Receptors (BCRs) similar to those of known bNAbs are not stimulated by vaccination with recombinant Env immunogens or that they become activated, but do not receive sufficient stimulation by vaccination to mature into bNAbs. This application aims to resolve a significant gap in our fundamental understanding of why the current generation of gp140 Env immunogens has failed to elicit bNAbs by following the stimulation and maturation of B cell receptors during vaccination with clade C gp140 immunogens.
Our application aims to resolve a significant gap in our fundamental understanding of why gp140 Env immunogens have failed to elicit bNAbs, by evaluating the stimulation, maturation and function of Envelope-specific B cell receptors during vaccination. As such, our proposed studies are highly significant to the eventual development of an effective vaccine against HIV-1.
|Vigdorovich, Vladimir; Oliver, Brian G; Carbonetti, Sara et al. (2016) Repertoire comparison of the B-cell receptor-encoding loci in humans and rhesus macaques by next-generation sequencing. Clin Transl Immunology 5:e93|
|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|
|Bricault, Christine A; Kovacs, James M; Nkolola, Joseph P et al. (2015) A multivalent clade C HIV-1 Env trimer cocktail elicits a higher magnitude of neutralizing antibodies than any individual component. J Virol 89:2507-19|
|Chang, Hui-Wen; Tartaglia, Lawrence J; Whitney, James B et al. (2015) Generation and evaluation of clade C simian-human immunodeficiency virus challenge stocks. J Virol 89:1965-74|