Induction of potent broadly-neutralizing antibodies (bNAbs) is a key for anti-HIV vaccine development. The boosting method for B-cell maturation toward bNAb induction has not been established, although recent studies have developed germline-targeting immunogens for priming. Here, we present a unique macaque model to analyze B-cell responses leading to anti-simian immunodeficiency virus (SIV) bNAb induction.
In our previous study, we obtained four rhesus macaques inducing potent anti-SIV bNAbs, VH3.33-restricted B404-class Abs, after SIVsmH635FC infection. In the present study, we examined B404-class Ab induction in six SIVsmH635FC-infected rhesus macaques. Monoclonal anti-SIV Fab clones were isolated from lymph nodes (LNs) by Bio-panning using phage display. B cell receptor (BCR) VH sequences derived from peripheral lymphocytes and LNs were analyzed by next generation sequencing (NGS).
B404-class Ab induction was observed in one of the six SIVsmH635FC-infected macaques but undetectable in the remaining five.Investigation of germline VH3.33 genes in five B404-class Ab inducers (one in the present study and four in the previous study) and five non-inducers revealed association of B404-class Ab induction with VH3.33 polymorphisms. Analysis of germline-reverted B404 mutants revealed that the VH3.33 residue 38 is the determinant for B404-class Ab induction. A B404-associated VH3.33 allele-positive macaque dominantly induced B404-class Abs even under undetectable viremia.
Our results first demonstrate restriction of bNAb induction by germline VH-gene polymorphism in a macaque AIDS model. Analysis using B404-associated VH3.33 allele-positive macaques could facilitate understanding of B-cell maturation leading to potent Ab induction.