Centre de Recherche du CHUM, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
Cell Host Microbe. 2019 Apr 10;25(4):578-587.e5. doi: 10.1016/j.chom.2019.03.002.
The HIV-1 envelope glycoprotein (Env) (gp120-gp41) is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection.
HIV-1 包膜糖蛋白（Env）（gp120-gp41）是中和抗体和抗体依赖的细胞细胞毒性（ADCC）的靶标。HIV-1 Env 具有柔韧性，可采样不同的构象状态。在与 CD4 结合之前，Env 采用封闭构象（状态 1），主要对抗体具有抗性。CD4 结合诱导中间状态（状态 2），随后是开放构象（状态 3），易受识别其他被封闭表位的抗体的结合。我们研究了在小分子 CD4 模拟化合物（CD4mc）存在下诱导 ADCC 的 Env 构象变化。我们发现了一种不对称的 Env 构象（状态 2A），被针对保守的 gp120 内部结构域的抗体识别，并介导 ADCC。来自 HIV+个体的血清含有这些抗体，它们可以与 CD4mc 结合稳定 Env 状态 2A。此外，在 HIV 感染的原代 CD4 T 细胞上触发状态 2A 会暴露诱导 ADCC 的表位。诱导这种 Env 构象的策略可能代表对抗 HIV-1 感染的方法。
