National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
1F32AI116355-01
United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
UM-1- AI100645
United States
Citation
Journal: Sci Transl Med / Year: 2017 Title: Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies. Authors: Mattia Bonsignori / Edward F Kreider / Daniela Fera / R Ryan Meyerhoff / Todd Bradley / Kevin Wiehe / S Munir Alam / Baptiste Aussedat / William E Walkowicz / Kwan-Ki Hwang / Kevin O ...Authors: Mattia Bonsignori / Edward F Kreider / Daniela Fera / R Ryan Meyerhoff / Todd Bradley / Kevin Wiehe / S Munir Alam / Baptiste Aussedat / William E Walkowicz / Kwan-Ki Hwang / Kevin O Saunders / Ruijun Zhang / Morgan A Gladden / Anthony Monroe / Amit Kumar / Shi-Mao Xia / Melissa Cooper / Mark K Louder / Krisha McKee / Robert T Bailer / Brendan W Pier / Claudia A Jette / Garnett Kelsoe / Wilton B Williams / Lynn Morris / John Kappes / Kshitij Wagh / Gift Kamanga / Myron S Cohen / Peter T Hraber / David C Montefiori / Ashley Trama / Hua-Xin Liao / Thomas B Kepler / M Anthony Moody / Feng Gao / Samuel J Danishefsky / John R Mascola / George M Shaw / Beatrice H Hahn / Stephen C Harrison / Bette T Korber / Barton F Haynes / Abstract: A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and ...A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.
G: DH270.1 single-chain variable fragment A: DH270.1 single-chain variable fragment C: DH270.1 single-chain variable fragment E: DH270.1 single-chain variable fragment
Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLN / Beg label comp-ID: GLN / End auth comp-ID: HIS / End label comp-ID: HIS / Auth seq-ID: 1 - 249 / Label seq-ID: 1 - 251
Dom-ID
Selection details
Auth asym-ID
Label asym-ID
1
chainA
A
B
2
chainC
C
C
3
chainE
E
D
4
chainG
G
A
-
Components
#1: Antibody
DH270.1single-chainvariablefragment
Mass: 27300.980 Da / Num. of mol.: 4 / Fragment: FAB Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Plasmid: pVRC-8400 / Cell line (production host): HEK 293T / Production host: Homo sapiens (human)
-
Experimental details
-
Experiment
Experiment
Method: X-RAY DIFFRACTION / Number of used crystals: 1
-
Sample preparation
Crystal
Density Matthews: 3.07 Å3/Da / Density % sol: 59.94 %
Crystal grow
Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.5 Details: 2.5 M sodium chloride, 100 mM sodium acetate, pH 4.5 and 200 mM LiSO4
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