Abstract
SummaryElicitation of HIV broadly neutralizing antibodies (bnAbs) is challenging because unmutated bnAb precursors are rare and seldom bind HIV envelope glycoprotein (Env) trimers. One strategy to initiate bnAb responses is to use germline-targeting (GT) immunogens with high affinity to bnAb-class precursor B cells and then shepherd affinity maturation with booster immunogens that successively look more like native Env. In a mouse model where the frequency of VRC01-precursor (VRC01gHL) B cells mimics that of humans, we show that following a GT HIV Env trimer protein prime, VRC01-class B cells in the germinal center (GC) acquire high-affinity VRC01-class B cell somatic hypermutations (SHMs). Many GC-derived VRC01gHL antibodies robustly bind N276 glycan-deficient Env trimers and neutralize several N276 glycan-deficient tier 2 HIV strains. These results are encouraging for GT Env trimer vaccine designs and demonstrate accumulation of substantial SHMs, including deletions, uncommon point mutations, and functional bnAb features, after a single immunization.
Highlights
Discovery of an efficacious vaccine against the human immunodeficiency virus (HIV) has been difficult because of the high mutability and diversity of HIV
Compared with minimalistic CD4bs GT immunogens like eOD-GT5 (Jardine et al, 2013), the CD4bs on the native envelope glycoprotein (Env) trimer is sterically occluded by adjacent protomers and surrounding glycans
We investigated whether augmenting CD4 T cell help would continue to influence factors such as late BGC kinetics, ongoing competition between VRC01gHL and polyclonal endogenous BGC cells, and somatic hypermutations (SHMs) of VRC01gHL B cells
Summary
Discovery of an efficacious vaccine against the human immunodeficiency virus (HIV) has been difficult because of the high mutability and diversity of HIV. Potent bnAbs are typically found in individuals chronically infected with HIV after years of infection and have more somatic hypermutations (SHMs) than usually elicited in response to vaccinations (Jardine et al, 2016b; Sok and Burton, 2018). One strategy involves priming with an immunogen that has a high binding affinity for predicted naive precursors of known bnAb-class B cells (Jardine et al, 2013). These germline-targeting (GT) immunogens would activate rare bnAb precursor B cells and induce germinal center (GC) responses (Mesin et al, 2016) to expand the population of bnAb precursors and initiate affinity maturation. Booster immunizations are administered sequentially to deliver immunogens more closely resembling the native Env trimer, guiding acquisition of SHMs needed for breadth and potency (Briney et al, 2016; Escolano et al, 2016; Jardine et al, 2016b; Steichen et al, 2016; Tian et al, 2016)
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