![]() ![]() Several GT priming immunogens have been designed specifically to bind the iGL versions of known bnAbs with high affinity 15, 16, 21, 22, 23, 24, 25, 26. Such priming immunogens are fittingly described as germline targeting (GT) priming immunogens 20, and a sequential vaccination strategy anchored by these priming immunogens has been described as “germline-targeting vaccine design” 21, 22. One theoretical approach to recapitulating bnAb responses via vaccination involves priming with an immunogen that has exceptionally high affinity for bnAb precursors, then sequentially introducing more native Env-like immunogens to drive bnAb class SHMs 19. This lack of affinity of bnAb precursors for wild-type HIV Env remains one of the main impediments in neutralizing antibody-directed HIV vaccine efforts. Making the problem even more challenging, inferred germline (iGL) precursors for many potent HIV bnAbs have been found to have very low or no detectable affinity for wild-type HIV Env 11, 12, 13, 14, 15, 16, 17, and wild-type Env immunogens have not succeeded in eliciting bnAb responses 18. Thus, vaccine priming of rare bnAb precursor B cells likely requires custom immunogens designed to bind specifically to targeted precursors 10. The majority of B cells in the human repertoire do not have BCRs with the potential to become HIV bnAbs. BnAb structural and genetic analyses have shown that many bnAb features required for broad and potent neutralization, such as specific CDR lengths 4, 5, 6, 7 and certain amino acid residues at fixed positions defined by immunoglobulin (IG) variable (V), diversity (D), or joining (J) gene usage 8, 9, are predetermined by recombined naive B cell receptors (BCRs). These antibodies achieve neutralization breadth and potency against diverse circulating clinical strains by accruing high numbers of somatic hypermutations (SHMs), allowing B cells to efficiently bind to conserved epitopes on the HIV Envelope viral spike protein (Env). Further, we analyzed IGHV1-2 allelic usage among three different cohorts we find that IGHV1-2 alleles traditionally thought to be incompatible with VRC01-class responses are relatively common in various human populations and that germline variation within IGHV1-2 associates with gene usage frequencies in the naive BCR repertoire.īroadly neutralizing antibodies (bnAbs) are present in a minority of patients chronically infected with human immunodeficiency virus-1 (HIV) 1, 2, 3. Using a germline-targeting eOD-GT8 immunogen and high-throughput droplet-based single-cell BCR sequencing, we demonstrate that large numbers of paired BCR sequences from multiple donors can be efficiently screened to elucidate precursor frequencies of rare, naive VRC01-class B cells. Knowledge of whether bnAb precursor B cells are circulating at sufficient frequencies within individuals in communities heavily impacted by HIV may be important. A successful HIV vaccine eliciting broadly neutralizing antibodies (bnAbs) must overcome the hurdle of being able to activate naive precursor B cells encoding features within their germline B cell receptors (BCR) that allow recognition of broadly neutralizing epitopes. ![]()
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