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 9...

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Published in:Cell 2016-04, Vol.165 (2), p.449-463
Main Authors: Bonsignori, Mattia, Zhou, Tongqing, Sheng, Zizhang, Chen, Lei, Gao, Feng, Joyce, M. Gordon, Ozorowski, Gabriel, Chuang, Gwo-Yu, Schramm, Chaim A., Wiehe, Kevin, Alam, S. Munir, Bradley, Todd, Gladden, Morgan A., Hwang, Kwan-Ki, Iyengar, Sheelah, Kumar, Amit, Lu, Xiaozhi, Luo, Kan, Mangiapani, Michael C., Parks, Robert J., Song, Hongshuo, Acharya, Priyamvada, Bailer, Robert T., Cao, Allen, Druz, Aliaksandr, Georgiev, Ivelin S., Kwon, Young D., Louder, Mark K., Zhang, Baoshan, Zheng, Anqi, Hill, Brenna J., Kong, Rui, Soto, Cinque, Mullikin, James C., Douek, Daniel C., Montefiori, David C., Moody, Michael A., Shaw, George M., Hahn, Beatrice H., Kelsoe, Garnett, Hraber, Peter T., Korber, Bette T., Boyd, Scott D., Fire, Andrew Z., Kepler, Thomas B., Shapiro, Lawrence, Ward, Andrew B., Mascola, John R., Liao, Hua-Xin, Kwong, Peter D., Haynes, Barton F.
Format: Article
Language:English
Subjects:
AIDS Vaccines - immunology
Amino Acid Sequence
Antibodies, Neutralizing - chemistry
Antibodies, Neutralizing - immunology
B-Lymphocytes - immunology
HIV Antibodies - chemistry
HIV Antibodies - immunology
HIV Envelope Protein gp120 - immunology
HIV Infections - immunology
HIV Infections - prevention & control
HIV-1 - immunology
Human immunodeficiency virus 1
Humans
Models, Molecular
Molecular Sequence Data
Sequence Alignment
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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 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. [Display omitted] •Developmental pathway of a CD4-mimicking antibody lineage from time of infection•Maturation involves focused recognition of CD4-binding site of vulnerability•Intrinsic VH1-46 gene mutability guides somatic mutation of CD4-binding site bnAbs•Study provided a strategy for inducing both CD4-mimicking and CDR H3-using bnAbs The complete life history of an HIV-1 broadly neutralizing antibody lineage, from the time of infection through development of its full potency and breadth, reveals key features that are common between HIV-1 antibodies from unrelated donors and that can be exploited to induce similar antibodies with vaccines.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2016.02.022