Egerer Lisa, Kiem Hans-Peter, von Laer Dorothee
Division of Virology, Department of Hygiene, Microbiology and Social Medicine, Medical University of Innsbruck, Peter Mayr-Str. 4b, Innsbruck, 6020, Austria,
Adv Exp Med Biol. 2015;848:191-209. doi: 10.1007/978-1-4939-2432-5_10.
Peptides derived from the C-terminal heptad repeat 2 region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very potent HIV-1 fusion inhibitors. Antiviral genes encoding either membrane-anchored (ma) or secreted (iSAVE) C peptides have been engineered and allow direct in vivo production of the therapeutic peptides by genetically modified host cells. Membrane-anchored C peptides expressed in the HIV-1 target cells by T-cell or hematopoietic stem cell gene therapy efficiently prevent virus entry into the modified cells. Such gene-protection confers a selective survival advantage and allows accumulation of the genetically modified cells. Membrane-anchored C peptides have been successfully tested in a nonhuman primate model of AIDS and were found to be safe in a phase I clinical trial in AIDS patients transplanted with autologous gene-modified T-cells. Secreted C peptides have the crucial advantage of not only protecting genetically modified cells from HIV-1 infection, but also neighboring cells, thus suppressing virus replication even if only a small fraction of cells is genetically modified. Accordingly, various cell types can be considered as potential in vivo producer cells for iSAVE-based gene therapeutics, which could even be modified by direct in vivo gene delivery in future. In conclusion, C peptide gene therapeutics may provide a strong benefit to AIDS patients and could present an effective alternative to current antiretroviral drug regimens.
源自HIV-1 gp41包膜糖蛋白C末端七肽重复序列2区域的肽，即所谓的C肽，是非常有效的HIV-1融合抑制剂。编码膜锚定（ma）或分泌型（iSAVE）C肽的抗病毒基因已被设计出来，可使转基因宿主细胞在体内直接产生治疗性肽。通过T细胞或造血干细胞基因疗法在HIV-1靶细胞中表达的膜锚定C肽能有效阻止病毒进入修饰细胞。这种基因保护赋予了选择性生存优势，并使转基因细胞得以积累。膜锚定C肽已在艾滋病非人灵长类动物模型中成功进行了测试，并且在接受自体基因修饰T细胞移植的艾滋病患者的I期临床试验中被发现是安全的。分泌型C肽的关键优势在于，它不仅能保护转基因细胞免受HIV-1感染，还能保护邻近细胞，从而即使只有一小部分细胞被基因修饰，也能抑制病毒复制。因此，各种细胞类型都可被视为基于iSAVE的基因治疗的潜在体内生产细胞，未来甚至可通过直接体内基因递送进行修饰。总之，C肽基因治疗可能会给艾滋病患者带来很大益处，并可能成为当前抗逆转录病毒药物治疗方案的有效替代方案。
