Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor na\xefve human B cells

Jeong Hyun Lee,Colin Havenar-Daughton,Laura Toy,Shane Crotty,Corey T Watson,William R Schief,Justin T Kos,Yana Safonova

doi:10.1038/s41541-021-00376-7

Abstract

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. Knowledge of whether bnAb precursor B cells are circulating at sufficient frequencies within individuals in communities heavily impacted by HIV may be important. 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. 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.

Highlights

Neutralizing antibodies are present in a minority of patients chronically infected with human immunodeficiency virus-1 (HIV)[1,2,3]
37–43% of the light chain (LC) paired with a IGHV1-2 heavy chain (HC) had a short 5 amino acids (5-AA) LCDR3 (42–50% IGKV and 0–21% IGL variable (IGLV), Fig. 1h, i)
The precursor frequency of VRC01-class naive B cells, defined as the from the human naive B cell repertoire and identified engineered outer domain (eOD)-GT8binding VRC01-class naive B cells by single-cell B cell receptors (BCR) sequencing to proportion of IGHV1-2 HC paired with a LC with a 5-AA LCDR3 among total naive B cells, ranged between 1 in 0.14 million to 0.28 million B cells (Table 2), similar to the previously reported frequency of 1 in 0.3 million B cells[36]

Summary

INTRODUCTION

Neutralizing antibodies (bnAbs) are present in a minority of patients chronically infected with human immunodeficiency virus-1 (HIV)[1,2,3]. The majority of B cells in the human repertoire do not have BCRs with the potential to become HIV bnAbs. vaccine priming of rare bnAb precursor B cells likely requires custom immunogens designed to bind to targeted precursors[10]. To determine whether droplet-based scRNA-seq was applicable trial as a GT priming immunogen HIV vaccine candidate to sequencing rare antigen-specific B cells, we sorted eOD-GT8-. We analyzed peripheral B cells from nine healthy donors (Table 1) using droplet-based scRNA-seq to obtain HC and LC paired VRC01-class naive human. BCR sequences and demonstrated that this method can reliably identify rare antigen-specific B cells We used these data along with other samples from ethnically diverse population cohorts to analyze the human population genetics of our VRC01-.

RESULTS

DISCUSSION

METHODS