Immunogenicity of a germline-targeting nanoparticle in knock-in mice expressing human B cell receptors of the HIV gp41 neutralizing antibody, DH511

Abstract

Abstract The Membrane Proximal External Region (MPER) of HIV Envelope represents a key target for vaccine development due to high neutralization breadth and potency of MPER-specific broadly neutralizing antibodies (bnAbs). However, neutralizing antibody responses to MPER epitopes are restricted by tolerance control and the MPER epitope is absent from many HIV immunogens under clinical investigation. Using computational design and yeast display, a candidate germline-targeting (GT5) immunogen was developed that bound strongly to the inferred human unmutated common ancestor (UCA) of the distal MPER bnAb DH511, as well as to several human DH511-like potential precursor antibodies. We studied the immunogenicity of a multimeric nanoparticle of the GT5 immunogen in a knock-in mouse line expressing human DH511.UCA B cell receptors (BCRs). Naïve DH511.UCA knock-in mice exhibited a reduction in overall B cell numbers, and DH511.UCA-bearing B cells expressed low levels of surface IgM and IgD, suggesting that DH511.UCA expression is subject to immune tolerance control. Nonetheless, following immunization with GT5 nanoparticles mixed with a saponin/monophosphoryl lipid A adjuvant, knock-in mice mounted robust anti-GT5 humoral responses, including anti-GT5 IgG in serum and GT5-specific germinal center B cells and T follicular helper cells in lymphoid tissues. Sequencing analysis of IgG+ GT5-specific B cells revealed improbable mutations in knock-in immunoglobulin genes of DH511.UCA. These studies will guide further optimization of immunogens with potential to select for development of bnAbs against MPER epitopes. Supported by a grant from NIH (P01-AI138211)