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

Summary for 5F96

• Entry DOI: 10.2210/pdb5f96/pdb
• Related: 4RWY 4RX4 4YFL
• Descriptor: clade A/E 93TH057 HIV-1 gp120 core, HEAVY CHAIN OF ANTIBODY CH235.12, LIGHT CHAIN OF ANTIBODY CH235.12, ... (6 entities in total)
• Functional Keywords: hiv-1, antibody, ch235 lineage, vh1-46 germline, immune system
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 3
• Total formula weight: 90351.21

Authors

Zhou, T.,Kwong, P.D. (deposition date: 2015-12-09, release date: 2016-03-09, Last modification date: 2020-07-29)

Primary citation

Bonsignori, M.,Zhou, T.,Sheng, Z.,Chen, L.,Gao, F.,Joyce, M.G.,Ozorowski, G.,Chuang, G.Y.,Schramm, C.A.,Wiehe, K.,Alam, S.M.,Bradley, T.,Gladden, M.A.,Hwang, K.K.,Iyengar, S.,Kumar, A.,Lu, X.,Luo, K.,Mangiapani, M.C.,Parks, R.J.,Song, H.,Acharya, P.,Bailer, R.T.,Cao, A.,Druz, A.,Georgiev, I.S.,Kwon, Y.D.,Louder, M.K.,Zhang, B.,Zheng, A.,Hill, B.J.,Kong, R.,Soto, C.,Mullikin, J.C.,Douek, D.C.,Montefiori, D.C.,Moody, M.A.,Shaw, G.M.,Hahn, B.H.,Kelsoe, G.,Hraber, P.T.,Korber, B.T.,Boyd, S.D.,Fire, A.Z.,Kepler, T.B.,Shapiro, L.,Ward, A.B.,Mascola, J.R.,Liao, H.X.,Kwong, P.D.,Haynes, B.F.
Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.
Cell, 165:449-463, 2016

PubMed 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.

PubMed: 26949186
DOI: 10.1016/j.cell.2016.02.022

Experimental method

X-RAY DIFFRACTION (2.2407 Å)