IFNα, a cytokine with multiple functions in innate and adaptive immunity and a potent inhibitor of HIV, exerts antiviral activity, in part, by enhancing apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family members. Although IFNα therapy is associated with reduced viral burden, this cytokine also mediates immune dysfunction and toxicities. Through detailed mapping of IFNα receptor binding sites, we generated IFNα hybrids and mutants and determined that structural changes in the C-helix alter the ability of IFN to limit retroviral activity. Selective IFNα constructs differentially block HIV replication and their directional magnitude of inhibition correlates with APOBEC3 levels. Importantly, certain mutants exhibited reduced toxicity as reflected by induced indoleamine 2,3-dioxygenase (IDO), suggesting discreet and shared intracellular signaling pathways. Defining IFN structure and function relative to APOBEC and other antiviral genes may enable design of novel IFN-related molecules preserving beneficial antiviral roles while minimizing negative effects.

中文翻译：

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IFN 的结构变异优先促进抗病毒功能


IFNα 是一种在先天性和适应性免疫中具有多种功能的细胞因子，也是一种有效的 HIV 抑制剂，其抗病毒活性部分是通过增强载脂蛋白 B mRNA 编辑酶催化多肽样 3 (APOBEC3) 家族成员来发挥的。尽管 IFNα 治疗与减少病毒负荷有关，但这种细胞因子也会介导免疫功能障碍和毒性。通过详细绘制 IFNα 受体结合位点，我们生成了 IFNα 杂合体和突变体，并确定 C 螺旋的结构变化改变了 IFN 限制逆转录病毒活性的能力。选择性 IFNα 构建体差异性地阻断 HIV 复制，其定向抑制程度与 APOBEC3 水平相关。重要的是，某些突变体表现出降低的毒性，如诱导的吲哚胺 2,3-双加氧酶 (IDO) 所反映的，这表明细胞内信号传导途径是谨慎且共享的。定义与 APOBEC 和其他抗病毒基因相关的 IFN 结构和功能，可能有助于设计新型 IFN 相关分子，保留有益的抗病毒作用，同时最大限度地减少负面影响。