Tan Suiyi, Li Wenjuan, Li Zhaofeng, Li Yujing, Luo Jiangyan, Yu Liangzhentian, Yang Jie, Qiu Mengjie, Cheng Hongyan, Xu Wei, Jiang Shibo, Lu Lu, Liu Shuwen, Ma Weifeng
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Microbiology, School of Public Health, Southern Medical University, Guangzhou 510515, China.
Viruses. 2019 Sep 18;11(9):874. doi: 10.3390/v11090874.
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 α-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.
CXC趋化因子受体4（CXCR4）是HIV-1进入靶细胞的共受体。其天然配体趋化因子SDF-1可抑制该受体介导的病毒进入。然而，CXCR4广泛的表达模式及其在各种生理和病理过程中的关键作用表明，直接将SDF-1作为进入抑制剂应用可能会产生严重后果。此前，我们通过删除SDF-1 C端功能区的α-螺旋构建了一种有效的SDF-1突变体SDF-1/54。值得注意的是，SDF-1/54的化学毒性能力显著降低，但对CXCR4的结合亲和力保持相似，这表明SDF-1/54可能更适合作为CXCR4抑制剂。在此，我们发现SDF-1/54对多种X4 HIV-1毒株具有强大的抗病毒活性，包括感染性克隆HIV-1 NL4-3、实验室适应株HIV-1 IIIB、临床分离株甚至耐药株。通过使用添加时间试验、非感染性和感染性细胞-细胞融合试验以及CXCR4内化试验，我们证明SDF-1/54是一种HIV-1进入抑制剂。SDF-1/54与几种抗逆转录病毒药物联合使用表现出强大的协同抗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显著影响。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作为HIV-1进入抑制剂可能具有治疗潜力。
