Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection

Abstract

HIV-1-neutralizing antibodies develop in most HIV-1-infected individuals, although highly effective antibodies are generally observed only after years of chronic infection. Here we characterize the rate of maturation and extent of diversity for the lineage that produced the broadly neutralizing antibody VRC01 through longitudinal sampling of peripheral B cell transcripts over 15 years and co-crystal structures of lineage members. Next-generation sequencing identified VRC01-lineage transcripts, which encompassed diverse antibodies organized into distinct phylogenetic clades. Prevalent clades maintained characteristic features of antigen recognition, though each evolved binding loops and disulfides that formed distinct recognition surfaces. Over the course of the study period, VRC01-lineage clades showed continuous evolution, with rates of ~2 substitutions per 100 nucleotides per year, comparable to that of HIV-1 evolution. This high rate of antibody evolution provides a mechanism by which antibody lineages can achieve extraordinary diversity and, over years of chronic infection, develop effective HIV-1 neutralization.

Optimization of the Solubility of HIV-1-Neutralizing Antibody 10E8 through Somatic Variation and Structure-Based Design

“…Broad HIV-1-neutralizing antibodies generally arise in highly diverse lineages with substantial somatic hypermutation (43); for example, the lineage of antibody VRC01 comprises at least four clades with sequence differences that could exceed 50% (44). Such lineage diversity provides a pool of somatic variants with distinct biological characteristics.…”

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

“…Longitudinal sampling of the antibodyome provides temporal resolution of antibody repertoire dynamics and of B‐cell ontogenies6, 7, 18 (Fig. 3A–C).…”

“…Antibodyomics2 has been used to investigate the antibodyome in animal models,23 comparing B‐cell responses to vaccination and infection. We have also conducted Antibodyomics2 analyses of antibody lineages for which the available data start only long after initial infection 18, 24. Although we were unable to infer the UCA for these lineages, the longitudinal data provided important insights into the continued evolution of a lineage even after many years and showed how an antibody lineage can split into multiple independently evolving clades 18, 24…”

“…For example, such analysis can reveal connections between antibody genotype, structural mode of recognition, and neutralization fingerprint similarity 39. Furthermore, the fingerprinting analysis can help trace the neutralization evolution of different members of the same antibody lineage 5, 18…”

“…To date, the maturation pathways of several broadly neutralizing antibody lineages have been characterized 6, 7, 8, 18, 22. Extensive efforts are being invested in the development of vaccines to mimic the natural antibody‐virus co‐evolution process, with the goal of eliciting similar broadly neutralizing antibodies 69.…”