The envelope glycoproteins (Envs) of HIV-1 are embedded in the cholesterol-rich lipid membrane of the virus. Chemical depletion of cholesterol from HIV-1 particles inactivates their infectivity. We observed that diverse HIV-1 strains exhibit a range of sensitivities to such treatment. Differences in sensitivity to cholesterol depletion could not be explained by variation in Env components known to interact with cholesterol, including the cholesterol-recognition motif and cytoplasmic tail of gp41. Using antibody-binding assays, measurements of virus infectivity, and analyses of lipid membrane order, we found that depletion of cholesterol from HIV-1 particles decreases the conformational stability of Env. It enhances exposure of partially cryptic epitopes on the trimer and increases sensitivity to structure-perturbing treatments such as antibodies and cold denaturation. Substitutions in the cholesterol-interacting motif of gp41 induced similar effects as depletion of cholesterol. Surface-acting agents, which are incorporated into the virus lipid membrane, caused similar effects as disruption of the Env-cholesterol interaction. Furthermore, substitutions in gp120 that increased structural stability of Env (i.e. induced a “closed” conformation of the trimer) increased virus resistance to cholesterol depletion and to the surface-acting agents. Collectively, these results indicate a critical contribution of the viral membrane to the stability of the Env trimer and to neutralization resistance against antibodies. Our findings suggest that the potency of poorly neutralizing antibodies, which are commonly elicited in vaccinated individuals, may be markedly enhanced by altering the lipid composition of the viral membrane.

中文翻译：

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HIV-1的脂质膜可稳定病毒包膜糖蛋白并调节其对抗体中和的敏感性

HIV-1的包膜糖蛋白（Envs）嵌入病毒的富含胆固醇的脂质膜中。HIV-1颗粒中胆固醇的化学消耗使它们的感染力失活。我们观察到，不同的HIV-1菌株对这种治疗表现出一定程度的敏感性。对胆固醇枯竭敏感性的差异无法通过已知与胆固醇相互作用的Env成分的变化来解释，其中包括gp41的胆固醇识别基序和细胞质尾巴。使用抗体结合测定，病毒感染性的测量和脂质膜顺序的分析，我们发现从HIV-1颗粒中胆固醇的消耗降低了Env的构象稳定性。它增强了三聚体上部分隐秘表位的暴露，并提高了对结构干扰处理（如抗体和冷变性）的敏感性。gp41与胆固醇相互作用的基序中的取代诱导的效应与胆固醇的消耗相似。掺入病毒脂质膜中的表面作用剂产生与破坏Env-胆固醇相互作用相似的作用。此外，gp120中增加Env结构稳定性（即引起三聚体“闭合”构象）的取代增加了病毒对胆固醇消耗和表面作用剂的抗性。总的来说，这些结果表明病毒膜对Env三聚体的稳定性和对抗体的中和抗性具有关键作用。