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

Abstract

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.

DOI: 10.1016/j.cell.2016.02.022

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@article{Bonsignori2016MaturationPF, title={Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody}, author={Mattia Bonsignori and Tongqing Zhou and Zizhang Sheng and Lei Chen and Feng Gao and M. Gordon Joyce and Gabriel Ozorowski and Gwo-Yu Chuang and Chaim A. Schramm and Kevin Wiehe and S. Munir Alam and Garnett Kelsoe and Morgan A. Gladden and Kwan-Ki Hwang and Sheelah Iyengar and Amit Kumar and Xiaozhi Lu and Kan Luo and Michael C. Mangiapani and Robert J. Parks and Hongshuo Song and Priyamvada Acharya and Robert T. Bailer and Allen Cao and Aliaksandr Druz and Ivelin S. Georgiev and Young Do Kwon and Mark K. Louder and Baoshan Zhang and Anqi Zheng and Brenna J. Hill and Rui Kong and Cinque Soto and James C. Mullikin and Daniel C. Douek and David C. Montefiori and M Anthony Moody and George M. Shaw and Beatrice H Hahn and Garnett H. Kelsoe and Peter T. Hraber and Bette T. Korber and Scott Boyd and Andrew Z Fire and Thomas B. Kepler and Lawrence Shapiro and Andrew B Ward and John R. Mascola and Hua-Xin Liao and Peter D. Kwong and Barton F. Haynes}, journal={Cell}, year={2016}, volume={165}, pages={449-463} }