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TitleStaged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.
Journal, issue, pagesSci Transl Med, Vol. 9, Issue 381, Year 2017
Publish dateMar 15, 2017
AuthorsMattia 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 /
PubMed AbstractA 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.
External linksSci Transl Med / PubMed:28298420 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.85 - 29.4 Å
Structure data

EMDB-8507:
92BR SOSIP.664 trimer in complex with DH270.1 Fab
Method: EM (single particle) / Resolution: 29.4 Å

PDB-5tpl:
Crystal Structure of DH270.3 (unliganded) from the DH270 Broadly Neutralizing N332-glycan Dependent Lineage
Method: X-RAY DIFFRACTION / Resolution: 2.5 Å

PDB-5tpp:
Crystal Structure of DH270.5 (unliganded) from the DH270 Broadly Neutralizing N332-glycan Dependent Lineage
Method: X-RAY DIFFRACTION / Resolution: 1.85 Å

PDB-5tqa:
Crystal Structure of DH270.6 (unliganded) from the DH270 Broadly Neutralizing N332-Glycan Dependent Lineage
Method: X-RAY DIFFRACTION / Resolution: 2.723 Å

PDB-5trp:
Crystal Structure of the Unliganded DH270 Cooperating Lineage Member DH272
Method: X-RAY DIFFRACTION / Resolution: 2.692 Å

PDB-5u0r:
Crystal Structure of DH270.UCA1 (unliganded) from the DH270 Broadly Neutralizing N332-glycan Dependent Lineage
Method: X-RAY DIFFRACTION / Resolution: 3.295 Å

PDB-5u0u:
Crystal Structure of DH270.1 (unliganded, single-chain Fv) from the DH270 Broadly Neutralizing N332-glycan Dependent Lineage
Method: X-RAY DIFFRACTION / Resolution: 3.428 Å

PDB-5u15:
Crystal Structure of DH270.UCA3 (unliganded) from the DH270 Broadly Neutralizing N332-glycan Dependent Lineage
Method: X-RAY DIFFRACTION / Resolution: 2.26 Å

Chemicals

ChemComp-HOH:
WATER

ChemComp-NA:
Unknown entry

ChemComp-CIT:
CITRIC ACID

ChemComp-SO4:
SULFATE ION

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • Human immunodeficiency virus 1
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / FAB FRAGMENT / HIV-1 / ANTIBODY / single-chain variable fragment

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