B cell repertoire sequencing of HIV-1 pediatric elite-neutralizers identifies multiple broadly neutralizing antibody clonotypes

Abstract

A limited subset of HIV–1 infected adult individuals typically after at least 2–3 years of chronic infection, develop broadly neutralizing antibodies (bnAbs), suggesting that highly conserved neutralizing epitopes on the HIV-1 envelope glycoprotein are difficult for B cell receptors to effectively target, during natural infection. Recent studies have shown the evolution of bnAbs in HIV–1 infected infants. We used bulk BCR sequencing (BCR–seq) to profile the B cell receptors from longitudinal samples (3 time points) collected from a rare pair of antiretroviral–naive, HIV–1 infected pediatric monozygotic twins (AIIMS–329 and AIIMS–330) who displayed elite plasma neutralizing activity against HIV–1. BCR–seq of both twins revealed convergent antibody characteristics including V–gene use, CDRH3 lengths and somatic hypermutation (SHM). Further, antibody clonotypes with genetic features similar to highly potent bnAbs isolated from adults showed ongoing development in donor AIIMS–330 but not in AIIMS–329, corroborating our earlier findings based on plasma bnAbs responses. An increase in SHM was observed in sequences of the IgA isotype from AIIMS–330. This study is an important step toward defining specific features of the antibody repertoire and shared clonotype maturation that are associated with the development of HIV-1 elite–neutralizing activity. Some of the shared lineages identified in this pair of identical twins, who had acquired HIV-1 infection by vertical transmission, may have been elicited by exposure to common HIV–1 antigens. Defining the sequences of such shared clonotypes in a large number of children can shed light on the role of specific B cell receptor features in the response to HIV–1 infection.