Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies

Abstract

Summary Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from CAPRISA-donor CAP256; each antibody contained the protruding tyrosine-sulfated, anionic antigen-binding loop (CDR H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30–38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation, an important vaccine insight.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…CAP256 was infected with a clade C TF virus and superinfected with a second clade C TF ~15 weeks after primary infection (63). The CAP256-VRC26 lineage was initiated by the superinfecting virus and the CAP256-VRC26.UCA was likely engaged by modestly mutated viruses (19, 64). …”

“…The B cell lineage immunogen design strategy is based on mapping the co-evolution of autologous virus and neutralizing lineages over time to select Env variants of the autologous virus quasispecies that participated in the selection of bnAb precursors by progressively engaging bnAb precursors, starting with the UCA and selection of immunogens with characteristics of Envs involved in natural induction of bnAbs in vivo (16–19, 64) (Korber, Hraber, Wagh and Hahn, this volume).…”

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).…”

“…We have also used Antibodyomics2 to investigate the origins of the CAP256‐VRC26 lineage, a V1V2‐targeting broadly neutralizing antibody 6, 19. We were able to identify autologous viruses that likely helped trigger lineage development and showed that toleration of early autologous escape mutants correlates strongly with the acquisition of breadth 19.…”

“…Our description is not intended to represent a comprehensive summary of the field; rather, we have been asked by the editors of this volume to synthesize key aspects and to focus on our specific contributions and ideas. The majority of the Antibodyomics technologies incorporate data generated by massively parallel next‐generation sequencing (NGS) of B‐cell transcripts to enhance the resolution of the genetic information underlying antibody development 5, 6, 7, 8, 9. We have also focused on technologies that allowed increased resolution of function relative to physical characteristics of antibodies and their targets.…”