Center for Infectious Disease Research, George Mason University, Manassas, Virginia, United States of America.
Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
PLoS Pathog. 2024 Aug 15;20(8):e1012448. doi: 10.1371/journal.ppat.1012448. eCollection 2024 Aug.
The chemokine co-receptors CXCR4 and CCR5 mediate HIV entry and signal transduction necessary for viral infection. However, to date only the CCR5 antagonist maraviroc is approved for treating HIV-1 infection. Given that approximately 50% of late-stage HIV patients also develop CXCR4-tropic virus, clinical anti-HIV CXCR4 antagonists are needed. Here, we describe a novel allosteric CXCR4 antagonist TIQ-15 which inhibits CXCR4-tropic HIV-1 infection of primary and transformed CD4 T cells. TIQ-15 blocks HIV entry with an IC50 of 13 nM. TIQ-15 also inhibits SDF-1α/CXCR4-mediated cAMP production, cofilin activation, and chemotactic signaling. In addition, TIQ-15 induces CXCR4 receptor internalization without affecting the levels of the CD4 receptor, suggesting that TIQ-15 may act through a novel allosteric site on CXCR4 for blocking HIV entry. Furthermore, TIQ-15 did not inhibit VSV-G pseudotyped HIV-1 infection, demonstrating its specificity in blocking CXCR4-tropic virus entry, but not CXCR4-independent endocytosis or post-entry steps. When tested against a panel of clinical isolates, TIQ-15 showed potent inhibition against CXCR4-tropic and dual-tropic viruses, and moderate inhibition against CCR5-tropic isolates. This observation was followed by a co-dosing study with maraviroc, and TIQ-15 demonstrated synergistic activity. In summary, here we describe a novel HIV-1 entry inhibitor, TIQ-15, which potently inhibits CXCR4-tropic viruses while possessing low-level synergistic activities against CCR5-tropic viruses. TIQ-15 could potentially be co-dosed with the CCR5 inhibitor maraviroc to block viruses of mixed tropisms.
趋化因子共受体 CXCR4 和 CCR5 介导 HIV 进入和信号转导，是病毒感染所必需的。然而，迄今为止，只有 CCR5 拮抗剂马拉韦罗被批准用于治疗 HIV-1 感染。鉴于大约 50%的晚期 HIV 患者也会发展成 CXCR4 嗜性病毒，因此需要临床用抗 HIV CXCR4 拮抗剂。在这里，我们描述了一种新型的变构 CXCR4 拮抗剂 TIQ-15，它能抑制原代和转化的 CD4 T 细胞中 CXCR4 嗜性 HIV-1 的感染。TIQ-15 以 13 nM 的 IC50 阻断 HIV 进入。TIQ-15 还抑制 SDF-1α/CXCR4 介导的 cAMP 产生、副肌球蛋白激活和趋化信号。此外，TIQ-15 诱导 CXCR4 受体内化，而不影响 CD4 受体的水平，这表明 TIQ-15 可能通过 CXCR4 上的新型变构位点发挥作用，从而阻断 HIV 进入。此外，TIQ-15 不抑制 VSV-G 假型 HIV-1 感染，表明其特异性阻断 CXCR4 嗜性病毒进入，而不阻断 CXCR4 非依赖性内吞或进入后步骤。在对一组临床分离株进行测试时，TIQ-15 对 CXCR4 嗜性和双嗜性病毒表现出强大的抑制作用，对 CCR5 嗜性分离株表现出中等抑制作用。随后进行了与马拉韦罗的联合用药研究，TIQ-15 表现出协同作用。总之，在这里我们描述了一种新型的 HIV-1 进入抑制剂 TIQ-15，它能有效抑制 CXCR4 嗜性病毒，同时对 CCR5 嗜性病毒具有低水平的协同作用。TIQ-15 可能与 CCR5 抑制剂马拉韦罗联合使用，以阻断混合嗜性病毒。
