Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

Abstract

SUMMARY Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%) and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary levels of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.

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

“…Defining cooperating B cell lineages and the virus escape mutants they select informs which virus Envs were involved in bnAb B cell lineage maturation and thus are candidates for inclusion in a vaccine (16). …”

“…The CH235 lineage progressed over 6 years of infection to extraordinary heterologous neutralization breadth (16). Like the 8ANC131 CD4 mimic bnAb, CH235 used V H 1-46 (16, 26).…”

“…The CH235 lineage progressed over 6 years of infection to extraordinary heterologous neutralization breadth (16). Like the 8ANC131 CD4 mimic bnAb, CH235 used V H 1-46 (16, 26). Co-crystal structural analysis revealed that the angle of approach to gp120 of the CH235 lineage antibodies was the same as for other VRC01-class of antibodies and did not change during bnAb affinity maturation (Figure 4A) (16).…”

“…As CH235 lineage antibodies progressed to broader and more potent neutralizing activity, they also increased their precision in targeting the CD4 binding supersite of vulnerability with progressively less interactions with the inner domain and the V5 loop (Figure 4B). Targeting precision correlated with neutralization breadth, and somatic hypermutation were necessary to focus antibody recognition of the CD4bs (16). These findings are relevant because they provide a structural approach to monitor antibody evolution and identify bnAb precursors elicited by vaccines.…”

“…CH235 lineage V H transcripts in blood B cells were found as early as 14 weeks post-transmission by next generation sequencing (NGS). The CH235 lineage interaction with HIV-1 Env loop D was mediated by hydrogen bonds between the side chains of Env N280 and CH235 CDR L3 (16). In particular, the N280 loop D mutations observed in the evolving autologous viruses were predicted to disrupt this H-bond network (16).…”