Cell. 2016 Apr 7; 165(2):449-63.

PubMed ID: 26949186

Maturation pathway from germline to broad HIV-1 neutralizer of a CD4-mimic antibody

Bonsignori M, Zhou T, Sheng Z, Chen L, Gao F, Joyce MG, Ozorowski G, Chuang GY, Schramm CA, Wiehe K, Alam SM, Bradley T, Gladden MA, Hwang KK, 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 HX, Kwong PD, Haynes BF

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.