Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth.

Deniz Cizmeci,Yann Chong Tan,Dongkyoon Kim,Galit Alter,Michael S Seaman,Guy Cavet,Boris Julg,Evan Rossignol,Ngan Nguyen,Giuseppe Lofano,Anne-Sophie Dugast

doi:10.7554/elife.62648

Deniz Cizmeci, Yann Chong Tan + Show 9 more

Open Access

https://doi.org/10.7554/elife.62648

Copy DOI

Abstract

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high-level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor (BCR) repertoires in 12,591 HIV-1 envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

Highlights

The induction of cross-reactive broadly neutralizing antibodies that can effectively neutralize a majority of circulating HIV-1 strains is a major goal of current HIV vaccine development, but no vaccine candidate to date has achieved this goal (Burton and Hangartner, 2016)
BNAbs with high potency and exquisite breadth against cross-clade viral isolates have been isolated from HIV-infected individuals who spontaneously control HIV to low plasma levels in the absence of antiretroviral therapy (‘HIV controllers’) (Walker et al, 2009; Simek et al, 2009; Gonzalez et al, 2018; Schoofs et al, 2019; Freund et al, 2017), suggesting that neutralizing antibody breadth may be achievable in the absence of high levels of viremia and rapidly evolving viral diversity, a scenario that more likely can be accomplished with vaccination strategies
Single HIV-1 Env-specific CD19+CD20+IgM-IgA-memory B-cells (MBCs) were FACS-sorted (Figure 1—figure supplement 2) and we obtained repertoires of natively paired, full variable region IGH and IGL by Immune Repertoire Capture analysis; 12,591 total sequence pairs were generated for all study participants, with 5771 sequences from TN and 2707 sequences from NN (Figure 1—figure supplement 2)

Summary

Introduction

The induction of cross-reactive broadly neutralizing antibodies (bNAbs) that can effectively neutralize a majority of circulating HIV-1 strains is a major goal of current HIV vaccine development, but no vaccine candidate to date has achieved this goal (Burton and Hangartner, 2016). BNAbs with high potency and exquisite breadth against cross-clade viral isolates have been isolated from HIV-infected individuals who spontaneously control HIV to low plasma levels in the absence of antiretroviral therapy (‘HIV controllers’) (Walker et al, 2009; Simek et al, 2009; Gonzalez et al, 2018; Schoofs et al, 2019; Freund et al, 2017), suggesting that neutralizing antibody breadth may be achievable in the absence of high levels of viremia and rapidly evolving viral diversity, a scenario that more likely can be accomplished with vaccination strategies. We performed a natively paired heavy and light chain B-cell receptor repertoire analysis of HIV-1 envelope (Env)-specific memory B-cells (MBCs) using high-throughput single-cell sequencing to determine alterations in the BCR Ig gene repertoire and B-cell clonal expansions that track with neutralization breadth

Results

Discussion

Materials and methods

Funding Funder