Department of Hygiene, Microbiology and Social Medicine, Division of Virology, Innsbruck Medical University, Innsbruck, Austria.
Mol Ther. 2011 Jul;19(7):1236-44. doi: 10.1038/mt.2011.30. Epub 2011 Mar 1.
Gene therapeutic strategies for human immunodeficiency virus type 1 (HIV-1) infection could potentially overcome the limitations of standard antiretroviral drug therapy (ART). However, in none of the clinical gene therapy trials published to date, therapeutic levels of genetic protection have been achieved in the target cell population for HIV-1. To improve systemic antiviral efficacy, C peptides, which are efficient inhibitors of HIV-1 entry, were engineered for high-level secretion by genetically modified cells. The size restrictions for efficient peptide export through the secretory pathway were overcome by expressing the C peptides as concatemers, which were processed into monomers by furin protease cleavage. These secreted antiviral entry inhibitory (SAVE) peptides mediated a substantial protective bystander effect on neighboring nonmodified cells, thus suppressing virus replication even if only a small fraction of cells was genetically modified. Accordingly, these SAVE peptides may provide a strong benefit to AIDS patients in future, and, if applied by direct in vivo gene delivery, could present an effective alternative to antiretroviral drug regimen.
基因治疗策略可用于治疗人类免疫缺陷病毒 1 型（HIV-1）感染，可能克服标准抗逆转录病毒药物治疗（ART）的局限性。然而，迄今为止，在已发表的所有临床基因治疗试验中，在 HIV-1 的靶细胞群体中都没有达到治疗水平的遗传保护。为了提高系统抗病毒疗效，设计了 C 肽，其作为 HIV-1 进入的有效抑制剂，通过基因修饰细胞进行高水平分泌。通过将 C 肽表达为串联体来克服通过分泌途径有效输出肽的大小限制，这些串联体通过弗林蛋白酶切割被加工成单体。这些分泌型抗病毒进入抑制（SAVE）肽对相邻的未修饰细胞产生了实质性的保护旁观者效应，从而抑制了病毒复制，即使只有一小部分细胞发生了基因修饰。因此，这些 SAVE 肽在未来可能会给艾滋病患者带来巨大的益处，如果通过直接体内基因递送应用，可能会成为抗逆转录病毒药物治疗方案的有效替代方法。
