Investigation of B cell and T follicular helper cell responses following priming with immunogens designed to trigger VRC01-class neutralizing antibodies to HIV-1

Antibodies are one of the host’s main defences against invading pathogens. There has yet to be a vaccine that can elicit antibodies capable of neutralizing a wide array of circulating Human Immunodeficiency Virus type-1 (HIV-1) strains. The general inability of germline (gl) precursors of these antibodies, termed broadly neutralizing antibodies (bnAbs), to bind recombinant forms of the Env spike used in prospective vaccine formulations has been identified as one of the likely obstacles to achieving a bnAb response by vaccination. The design of antigens that can engage gl precursors of bnAbs, dubbed “gl targeting”, is a strategy currently being explored to elicit bnAbs. The VRC01-class of bnAbs, which target the highly conserved CD4 binding site on the HIV Env spike, are attractive templates for vaccine design owing to their tremendous neutralization potency and breadth and common mode of antigen recognition. Here, we investigated a panel of antigens, derived from the 45_01dG5 strain of HIV-1, for their ability to engage VRC01-class gl precursors. Additionally, we assessed their capacity to stimulate T follicular helper (Tfh) cell and B cell responses in C57BL/6 mice after a single immunization, using assays developed with two model immunogens. Specifically, we assessed the influence, on Tfh and B cell responses, of appending a single copy of the PanDR helper epitope (PADRE) to select immunogens. We found that several constructs bind mature and gl-reverted versions of the VRC01 bnAb, as well as one of two VRC01-class precursor antibodies tested here. The immunizations revealed that immunogens with a glycan-masked V3 elicit a very weak Tfh response, which may have led to correspondingly weak B cell responses. Appendage of the single PADRE motif was insufficient to reverse the otherwise weak Tfh cell responses observed with the V3-masked immunogens used here, supporting the need for multiple copies of the motif to adequately provide Tfh cell mediated B cell help. In sum, this work provides insight into the early immune response to priming by HIV-1 candidate immunogens as part of a first phase of explorations toward eliciting VRC01-class bnAbs.