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-Structure paper
タイトル | Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. |
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ジャーナル・号・ページ | Cell, Vol. 165, Issue 2, Page 449-463, Year 2016 |
掲載日 | 2016年4月7日 |
著者 | Mattia Bonsignori / Tongqing Zhou / Zizhang Sheng / Lei Chen / Feng Gao / M Gordon Joyce / Gabriel Ozorowski / Gwo-Yu Chuang / Chaim A Schramm / Kevin Wiehe / S Munir Alam / Todd Bradley / Morgan A Gladden / Kwan-Ki Hwang / Sheelah Iyengar / Amit Kumar / Xiaozhi Lu / Kan Luo / Michael C Mangiapani / Robert J Parks / Hongshuo Song / Priyamvada Acharya / Robert T Bailer / Allen Cao / Aliaksandr Druz / Ivelin S Georgiev / Young D Kwon / Mark K Louder / Baoshan Zhang / Anqi Zheng / Brenna J Hill / Rui Kong / Cinque Soto / / James C Mullikin / Daniel C Douek / David C Montefiori / Michael A Moody / George M Shaw / Beatrice H Hahn / Garnett Kelsoe / Peter T Hraber / Bette T Korber / Scott D Boyd / Andrew Z Fire / Thomas B Kepler / Lawrence Shapiro / Andrew B Ward / John R Mascola / Hua-Xin Liao / Peter D Kwong / Barton F Haynes / |
PubMed 要旨 | 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 ...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. |
リンク | Cell / PubMed:26949186 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 1.86 - 25.0 Å |
構造データ | EMDB-8078: EMDB-8079: EMDB-8080: EMDB-8081: EMDB-8082: EMDB-8083: PDB-5f96: PDB-5f9o: PDB-5f9w: |
化合物 | ChemComp-NAG: ChemComp-EPE: ChemComp-HOH: ChemComp-15P: ChemComp-PO4: |
由来 |
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キーワード | IMMUNE SYSTEM / HIV-1 / Antibody / CH235 lineage / VH1-46 germline / antibody evolution HIV-1 broadly neutralizing CD4 binding site / neutralizing antibody / CH235 |