Germline B cell receptor of BG18-class V3-glycan-directed broadly neutralizing antibody (BG18-class gBCR)

The germline B cell receptors (gBCRs) of the BG18-class are the unmutated precursors of potent broadly neutralizing antibodies (bnAbs) that target the V3-glycan supersite on the HIV-1 Envelope (Env) protein (Steichen et al., 2019). These receptors are characterized by specific genetic features, including the usage of VH4-4 and VL3-25 genes and a long heavy chain complementarity determining region 3 (HCDR3) that recognizes the conserved GDIR peptide motif and the N332 glycan (Freund et al., 2017). In the context of HIV-1 vaccine development, these gBCRs are the primary targets for germline-targeting immunogens, such as N332-GT5, which are engineered to bind with high affinity to the germline receptors to overcome the lack of affinity between native HIV-1 Env and naive B cell precursors (Steichen et al., 2024). By binding these rare gBCRs, the immunogens trigger B cell activation and initiate the complex process of somatic hypermutation and affinity maturation (Kalyuzhniy et al., 2024). This strategy aims to guide the immune system to produce mature bnAbs capable of neutralizing a wide range of HIV-1 strains, which is a critical goal for a protective HIV vaccine (Ma et al., 2024). Therapeutic challenges include the extreme rarity of these precursors in the human B cell repertoire and the potential for competition with other B cell lineages that target non-neutralizing epitopes (Steichen et al., 2016).

Other names

BG18 germline precursorBG18-class unmutated common ancestor (UCA)V3-glycan-directed bNAb precursorBG18-class naive B cell receptorBG18-class precursor B cell receptor

Germline targeting and priming of specific B cell lineages to initiate somatic hypermutation and affinity maturation toward broadly neutralizing antibodies.