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.
Bonsignori, M; Zhou, T; Sheng, Z; Chen, L; Gao, F; Joyce, MG; Ozorowski, G; Chuang, G-Y; Schramm, CA; Wiehe, K; Alam, SM; Bradley, T; Gladden, MA; Hwang, K-K; Iyengar, S; Kumar, A; Lu, X; Luo, K; Mangiapani, MC; Parks, RJ; Song, H; Acharya, P; Bailer, RT; Cao, A; Druz, A; Georgiev, IS; Kwon, YD; Louder, MK; Zhang, B; Zheng, A; Hill, BJ; Kong, R; Soto, C; NISC Comparative Sequencing Program, ; Mullikin, JC; Douek, DC; Montefiori, DC; Moody, MA; Shaw, GM; Hahn, BH; Kelsoe, G; Hraber, PT; Korber, BT; Boyd, SD; Fire, AZ; Kepler, TB; Shapiro, L; Ward, AB; Mascola, JR; Liao, H-X; Kwong, PD; Haynes, BF
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