Maturation Pathway from Germline to Broad HIV 1 Neutralizer of a CD4 Mimic Antibody
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 level 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.
Cell