Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides
Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides
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DOI：
10.1128/jvi.78.2.568-575.2004
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发表时间：
2004-01-01
影响因子：
5.4
通讯作者：
von Laer, D
中科院分区：
文献类型：
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作者：
Egelhofer, M;Brandenburg, G;von Laer, D
随着抗逆转录病毒药物治疗的局限性，如毒性和耐药性，变得明显，对人类免疫缺陷病毒（HIV）感染的替代治疗方法的兴趣正在增长。我们开发了第一个针对广泛的HIV-1型（HIV-1）变异进入的基因治疗策略。在膜融合水平上，通过逆转录病毒表达一种由HIV-1 gp41跨膜糖蛋白的第二个七重复序列衍生的膜锚定肽，可以抑制感染。为了达到最大的表达和抗病毒活性，优化了肽本身、在细胞表面呈现肽的支架和逆转录病毒载体骨架。该优化结构可有效抑制病毒在细胞系和原代血淋巴细胞中的复制。膜锚定的C肽也被证明可以与游离的gp41 N肽结合，这表明膜锚定的抗病毒C肽具有与游离gp41 N肽相似的作用模式。该抗病毒载体的临床前毒性和疗效研究已经完成，临床试验正在准备中。
As the limitations of antiretroviral drug therapy, such as toxicity and resistance, become evident, interest in alternative therapeutic approaches for human immunodeficiency virus (HIV) infection is growing. We developed the first gene therapeutic strategy targeting entry of a broad range of HIV type 1 (HIV-1) variants. Infection was inhibited at the level of membrane fusion by retroviral expression of a membrane-anchored peptide derived from the second heptad repeat of the HIV-1 gp41 transmembrane glycoprotein. To achieve maximal expression and antiviral activity, the peptide itself, the scaffold for presentation of the peptide on the cell surface, and the retroviral vector backbone were optimized. This optimized construct effectively inhibited virus replication in cell lines and primary blood lymphocytes. The membrane-anchored C-peptide was also shown to bind to free gp41 N peptides, suggesting that membrane-anchored antiviral C peptides have a mode of action similar to that of free gp41 C peptides. Preclinical toxicity and efficacy studies of this antiviral vector have been completed, and clinical trials are in preparation.