National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
HIVRAD P01 AI100148
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
P50 GM082545-06
米国
引用
ジャーナル: Cell / 年: 2020 タイトル: Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody. 著者: Philipp Schommers / Henning Gruell / Morgan E Abernathy / My-Kim Tran / Adam S Dingens / Harry B Gristick / Christopher O Barnes / Till Schoofs / Maike Schlotz / Kanika Vanshylla / Christoph ...著者: Philipp Schommers / Henning Gruell / Morgan E Abernathy / My-Kim Tran / Adam S Dingens / Harry B Gristick / Christopher O Barnes / Till Schoofs / Maike Schlotz / Kanika Vanshylla / Christoph Kreer / Daniela Weiland / Udo Holtick / Christof Scheid / Markus M Valter / Marit J van Gils / Rogier W Sanders / Jörg J Vehreschild / Oliver A Cornely / Clara Lehmann / Gerd Fätkenheuer / Michael S Seaman / Jesse D Bloom / Pamela J Bjorkman / Florian Klein / 要旨: Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits ...Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new V1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
全体 : Complex of three bNAb 1-55 Fabs and three 10-1074 Fabs bound to R...
全体
名称: Complex of three bNAb 1-55 Fabs and three 10-1074 Fabs bound to RC1 variant of BG505 SOSIP.664 trimer
要素
複合体: Complex of three bNAb 1-55 Fabs and three 10-1074 Fabs bound to RC1 variant of BG505 SOSIP.664 trimer
複合体: 10-1074 Fab
タンパク質・ペプチド: 10-1074 Fab Heavy Chain
タンパク質・ペプチド: 10-1074 Fab Light Chain
複合体: 1-55 Fab
タンパク質・ペプチド: 1-55 Fab Heavy Chain
タンパク質・ペプチド: 1-55 Fab Light Chain
複合体: RC1 variant of HIV-1 BG505 SOSIP.664
タンパク質・ペプチド: RC1 variant of HIV-1 Env glycoprotein gp120
タンパク質・ペプチド: RC1 variant of HIV-1 Env glycoprotein gp41
リガンド: 2-acetamido-2-deoxy-beta-D-glucopyranose
+
超分子 #1: Complex of three bNAb 1-55 Fabs and three 10-1074 Fabs bound to R...
超分子
名称: Complex of three bNAb 1-55 Fabs and three 10-1074 Fabs bound to RC1 variant of BG505 SOSIP.664 trimer タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6
凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 295 K / 装置: FEI VITROBOT MARK IV 詳細: 0 blot force, 3.5 second blot time, 3 uL sample added to freshly glow-discharged grids.
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電子顕微鏡法
顕微鏡
FEI TALOS ARCTICA
撮影
フィルム・検出器のモデル: FEI FALCON III (4k x 4k) 検出モード: COUNTING / 撮影したグリッド数: 1 / 実像数: 684 / 平均電子線量: 40.0 e/Å2