A Novel CXCR4 Targeting Protein SDF-1/54 as an HIV-1 Entry Inhibitor
A Novel CXCR4 Targeting Protein SDF-1/54 as an HIV-1 Entry Inhibitor
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新型 CXCR4 靶向蛋白 SDF-1/54 作为 HIV-1 进入抑制剂
DOI：
10.3390/v11090874
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发表时间：
2019-09-01
期刊：
影响因子：
4.7
通讯作者：
Ma, Weifeng
中科院分区：
文献类型：
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作者：
Tan, Suiyi;Li, Wenjuan;Ma, Weifeng
CXC趋化因子受体4（CXCR 4）是HIV-1进入靶细胞的共受体。其天然配体，趋化因子SDF-1，抑制由该受体介导的病毒进入。然而，CXCR 4的广泛表达模式及其在各种生理和病理过程中的关键作用表明，直接应用SDF-1作为进入抑制剂可能会产生严重的后果。在此之前，我们构建了一个有效的SDF-1突变体，SDF-1/54，通过删除SDF-1的C-末端功能区的α-螺旋。值得注意的是，SDF-1/54显示出显著降低的化学毒性能力，但与CXCR 4保持相似的结合亲和力，表明SDF-1/54可能更好地用作CXCR 4抑制剂。在这里，我们发现SDF-1/54对各种X4 HIV-1毒株表现出有效的抗病毒活性，包括感染性克隆HIV-1 NL 4 -3、实验室适应毒株HIV-1 IIIB、临床分离株甚至耐药毒株。通过添加时间试验、非感染性和感染性细胞-细胞融合试验和CXCR 4内化试验，我们证明SDF-1/54是HIV-1进入抑制剂。SDF-1/54与几种抗逆转录病毒药物的组合显示出有效的协同抗HIV-1活性。此外，SDF-1/54稳定，其抗HIV-1活性不受精液、阴道液模拟物和人血清白蛋白的影响。SDF-1/54对淋巴细胞和阴道上皮细胞的体外细胞毒性有限。基于这些发现，SDF-1/54可能具有作为HIV-1进入抑制剂的治疗潜力。
CXC chemokine receptor 4 (CXCR4) is a co-receptor for HIV-1 entry into target cells. Its natural ligand, the chemokine SDF-1, inhibits viral entry mediated by this receptor. However, the broad expression pattern of CXCR4 and its critical roles in various physiological and pathological processes indicate that the direct application of SDF-1 as an entry inhibitor might have severe consequences. Previously, we constructed an effective SDF-1 mutant, SDF-1/54, by deleting the alpha-helix of the C-terminal functional region of SDF-1. Of note, SDF-1/54 shows remarkable decreased chemotoxic ability, but maintains a similar binding affinity to CXCR4, suggesting SDF-1/54 might better serve as a CXCR4 inhibitor. Here, we found that SDF-1/54 exhibited potent antiviral activity against various X4 HIV-1 strains, including the infectious clone HIV-1 NL4-3, laboratory-adapted strain HIV-1 IIIB, clinical isolates and even drug-resistant strains. By using time-of-addition assay, non-infectious and infectious cell-cell fusion assay and CXCR4 internalization assay, we demonstrated SDF-1/54 is an HIV-1 entry inhibitor. A combination of SDF-1/54 with several antiretroviral drugs exhibited potent synergistic anti-HIV-1 activity. Moreover, SDF-1/54 was stable and its anti-HIV-1 activity was not significantly affected by the presence of seminal fluid, vaginal fluid simulant and human serum albumin. SDF-1/54 showed limited in vitro cytotoxicity to lymphocytes and vaginal epithelial cells. Based on these findings, SDF-1/54 could have a therapeutic potential as an HIV-1 entry inhibitor.