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-Structure paper
タイトル | Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability. |
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ジャーナル・号・ページ | Immunity, Vol. 51, Issue 5, Page 915-929.e7, Year 2019 |
掲載日 | 2019年11月19日 |
著者 | Viktoriya Dubrovskaya / Karen Tran / Gabriel Ozorowski / Javier Guenaga / Richard Wilson / Shridhar Bale / Christopher A Cottrell / Hannah L Turner / Gemma Seabright / Sijy O'Dell / Jonathan L Torres / Lifei Yang / Yu Feng / Daniel P Leaman / Néstor Vázquez Bernat / Tyler Liban / Mark Louder / Krisha McKee / Robert T Bailer / Arlette Movsesyan / Nicole A Doria-Rose / Marie Pancera / Gunilla B Karlsson Hedestam / Michael B Zwick / Max Crispin / John R Mascola / Andrew B Ward / Richard T Wyatt / |
PubMed 要旨 | The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are ...The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination. |
リンク | Immunity / PubMed:31732167 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.296 - 30.0 Å |
構造データ | EMDB-20259, PDB-6p62: EMDB-20260, PDB-6p65: EMDB-20273: EMDB-20274: EMDB-20279: EMDB-20280: EMDB-20342: EMDB-20343: EMDB-20344: EMDB-20345: EMDB-20346: EMDB-20347: PDB-6peh: |
化合物 | ChemComp-NAG: ChemComp-SO4: ChemComp-HOH: |
由来 |
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キーワード | VIRAL PROTEIN/immune system / HIV-1 / CD4 binding site / neutralizing antibody / rabbit antibody / VIRAL PROTEIN / VIRAL PROTEIN-immune system complex / IMMUNE SYSTEM / Antibody / bnAb / HIV |