eCD4-immunoglobulin (Ig) is an HIV entry inhibitor that mimics the engagement of both CD4 and CCR5 with the HIV envelope (Env) protein, a property that imbues it with remarkable potency and breadth. However, env is exceptionally genetically malleable and can evolve to escape a wide variety of entry inhibitors. Here we document the evolution of partial eCD4-Ig resistance in SHIV-AD8EO-infected rhesus macaques (RMs) treated with adeno-associated virus vectors encoding eCD4-Ig. In one RM, setpoint viremia plateaued at 1,000 vRNA copies/mL, despite concomitant serum concentrations of eCD4-Ig in the 60–110 μg/mL range, implying that the virus had gained partial eCD4-Ig resistance. Env mutations occurring prominently in this animal were cloned and further characterized. Three of these mutations (R315G, A436T, and G471E) were sufficient to confer substantial resistance to eCD4-Ig-mediated neutralization onto the parental Env, accompanied by a marked loss of viral fitness. This resistance was not driven by decreased CD4 affinity, subverted sulfopeptide mimicry, changes to co-receptor tropism, or by a gain of CD4 independence. Rather, our data argue that the Env evolving in this animal attained eCD4-Ig resistance by decreasing triggerability, stabilizing the triggered state, and changing the nature of its relationship to the host CD4.

中文翻译：

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AAV 载体递送 eCD4-Ig 后 SHIV-AD8EO 感染的恒河猴 env 的体内进化


eCD4-免疫球蛋白 （Ig） 是一种 HIV 进入抑制剂，可模拟 CD4 和 CCR5 与 HIV 包膜 （Env） 蛋白的结合，这一特性使其具有非凡的效力和广度。然而，env 在遗传上具有极强的可塑性，并且可以进化以逃避多种进入抑制剂。在这里，我们记录了用编码 eCD4-Ig 的腺相关病毒载体处理的 SHIV-AD8EO 感染的恒河猴 （RM） 中部分 eCD4-Ig 耐药性的演变。在一个 RM 中，尽管伴随的 eCD4-Ig 血清浓度在 60-110 μg/mL 范围内，但设定点病毒血症稳定在 1,000 个 vRNA 拷贝/mL，这意味着病毒已获得部分 eCD4-Ig 耐药性。克隆并进一步表征了在该动物中突出发生的 env 突变。其中三个突变 （R315G、A436T 和 G471E） 足以赋予亲本 Env 对 eCD4-Ig 介导的中和的实质性抵抗力，并伴有病毒适应性的显着丧失。这种耐药性不是由 CD4 亲和力降低、磺肽模拟被破坏、共受体趋向性变化或 CD4 独立性增加驱动的。相反，我们的数据认为，这种动物体内进化的 Env 通过降低触发性、稳定触发状态和改变其与宿主 CD4 的关系性质而获得了 eCD4-Ig 抗性。