Co-evolution of HIV-1 CD4 binding site-specific broadly neutralizing antibody lineage VRC13 and autologous virus reveals pressures driving differential lineage breadth and virus escape

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B961
Abstract ID: 7572

Presenting Author:
Zoe Vrakas , Postbac Research Fellow at NIAID, NIH, NIH

Abstract:

Broadly neutralizing antibody lineages (bnAbs) capable of recognizing diverse, globally distributed HIV-1 strains develop in a subset of chronically infected individuals by antibody:autologous virus co-evolution. The mechanism of autologous virus evolution driving the development of broadly reactive antibody sublineages, as distinguished from narrow-breadth sublineages, remains a focus of HIV-1 vaccine research.  Here, we describe the coevolution of VRC13, a CD4 binding-site (CD4bs)-targeting bnAb lineage, with autologous virus from donor NIH44. VRC13.01 neutralizes 83% of 208 globally distributed virus isolates, making it among the broadest CDRH3-mediated CD4bs-specific Abs characterized. Isolation of additional members of VRC13 family sublineages via antigen probe sorts reveal phylogenetic segregation into a "broad branch" achieving 70-94% breadth against a 30-virus panel, and a "narrow branch" with ~30% breadth. The sensitivity of NIH44 autologous viruses to broad- versus narrow-branch isolates contradicts heterologous virus sensitivity, as evaluated using the TZM-bl assay. Narrow branch isolates exhibited greater potency against autologous viruses compared to broad branch isolates. Pressures driving neutralization breadth of Abs and analyses of viral sequences display escape of viruses that help inform lineage-based vaccine design to limit maturation of "off-track" antibodies while promoting development of sublineages capable of cross-neutralizing diverse HIV-1 isolates.