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TitleMaturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.
Journal, issue, pagesCell, Vol. 165, Issue 2, Page 449-463, Year 2016
Publish dateApr 7, 2016
AuthorsMattia 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 AbstractAntibodies 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.
External linksCell / PubMed:26949186 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.86 - 25.0 Å
Structure data

EMDB-8078:
BG505 SOSIP.664 HIV-1 Env trimer in complex with anti-HIV CH235.12 wk323 Fab
Method: EM (single particle) / Resolution: 17.0 Å

EMDB-8079:
B41 SOSIP.664 HIV-1 Env trimer in complex with anti-HIV CH235.12 wk323 Fab
Method: EM (single particle) / Resolution: 16.0 Å

EMDB-8080:
B41 SOSIP.664 HIV-1 Env trimer in complex with anti-HIV CH235.9 wk152 Fab
Method: EM (single particle) / Resolution: 19.0 Å

EMDB-8081:
BG505 SOSIP.664 HIV-1 Env trimer in complex with anti-HIV CH235.9 wk152 Fab
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-8082:
BG505 SOSIP.664 HIV-1 Env trimer in complex with anti-HIV CH235 wk41 Fab
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-8083:
B41 SOSIP.664 HIV-1 Env trimer in complex with anti-HIV CH235 wk41 Fab
Method: EM (single particle) / Resolution: 24.0 Å

PDB-5f96:
Crystal structure of broadly neutralizing VH1-46 germline-derived CD4-binding site-directed antibody CH235.12 in complex with HIV-1 clade A/E 93TH057 gp120
Method: X-RAY DIFFRACTION / Resolution: 2.2407 Å

PDB-5f9o:
Crystal structure of broadly neutralizing VH1-46 germline-derived CD4-binding site-directed antibody CH235.09 in complex with HIV-1 clade A/E 93TH057 gp120
Method: X-RAY DIFFRACTION / Resolution: 1.86 Å

PDB-5f9w:
Crystal structure of broadly neutralizing VH1-46 germline-derived CD4-binding site-directed antibody CH235 in complex with HIV-1 clade A/E 93TH057 gp120
Method: X-RAY DIFFRACTION / Resolution: 2.8911 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-EPE:
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / pH buffer*YM / HEPES

ChemComp-HOH:
WATER / Water

ChemComp-15P:
POLYETHYLENE GLYCOL (N=34) / precipitant*YM / Polyethylene glycol

ChemComp-PO4:
PHOSPHATE ION / Phosphate

Source
  • human immunodeficiency virus 1
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / HIV-1 / Antibody / CH235 lineage / VH1-46 germline / antibody evolution HIV-1 broadly neutralizing CD4 binding site / neutralizing antibody / CH235

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