TLR7 Activation of Macrophages by Imiquimod Inhibits HIV Infection through Modulation of Viral Entry Cellular Factors.
TLR7 Activation of Macrophages by Imiquimod Inhibits HIV Infection through Modulation of Viral Entry Cellular Factors.
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DOI：
10.3390/biology10070661
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发表时间：
2021-07-13
期刊：
影响因子：
4.2
通讯作者：
Ho WZ
中科院分区：
文献类型：
--
作者：
Meng FZ;Liu JB;Wang X;Wang P;Hu WH;Hou W;Ho WZ
Toll样受体(TLR)7由包括巨噬细胞在内的免疫细胞高度表达。TLR7激动剂是有吸引力的治疗药物，因为它们具有激活针对病毒感染的先天性和获得性免疫的潜力。咪喹莫特是一种特异性的TLR7激动剂，已成功用于免疫功能正常个体的生殖器/肛周尖锐湿疣的局部治疗。在这里，我们检测了咪喹莫特在原代人巨噬细胞中的抗HIV作用，并证明了咪喹莫特激活TLR7可以有效地抑制不同HIV毒株对细胞的感染。进一步的机制研究表明，虽然咪喹莫特对干扰素的表达几乎没有影响，但它对巨噬细胞的处理导致了CC趋化因子的产生，而CC趋化因子是HIV进入共同受体CCR5的天然配体，而CD4和CCR5的表达则减少了。这些发现具有重要的临床意义，并表明咪喹莫特激活细胞内抗病毒免疫具有开发基于TLR7激动剂的HIV感染治疗的潜力。Toll样受体(TLR)7是一种检测单链核糖核酸(SsRNA)的病毒传感器，它的激活可以诱导细胞内对病毒感染的天然免疫。咪喹莫特是一种TLR7的合成配体，已成功用于免疫功能正常的人的生殖器/肛周尖锐湿疣的局部治疗。我们研究了咪喹莫特对人免疫缺陷病毒(HIV)感染原代人巨噬细胞的影响，证明咪喹莫特处理细胞能有效地抑制多种HIV株(Bal、YU2和Jago)的感染。当巨噬细胞在感染前接受治疗时，咪喹莫特的这种抗HIV活性最强。用假型HIVNL4-3-ΔEnv-EGFP-Bal感染巨噬细胞，结果表明咪喹莫特能阻断病毒入侵。进一步的机制研究表明，虽然咪喹莫特对干扰素(IFN)的表达几乎没有影响，但它对巨噬细胞的处理导致了CC趋化因子(人巨噬细胞炎性蛋白-1α(MIP-1α)、MIP-1β和激活时调节的正常T细胞表达和分泌(RANTES))的产生，这是HIV进入联合受体CCR5的天然配体，并降低了CD4和CCR5的表达。巨噬细胞培养中加入针对CC趋化因子的抗体可以阻断咪喹莫特介导的HIV抑制。这些发现为TLR7参与巨噬细胞抗HIV的细胞内免疫提供了实验证据，表明咪喹莫特在治疗HIV感染者生殖器/肛周尖锐湿疣方面的额外好处值得进一步的临床评估。
The Toll-like receptor (TLR) 7 is highly expressed by immune cells including macrophages. Agonists to TLR7 are attractive therapeutic agents as they have the potential of activating both innate and acquired immunity against viral infections. Imiquimod, a specific TLR7 agonist, has been successfully used for the topical treatment of genital/perianal warts in immunocompetent individuals. Here we examined the anti-HIV effect of imiquimod in primary human macrophages and demonstrated that TLR7 activation by imiquimod could effectively inhibit infection of the cells by different strains of HIV. Further mechanistic studies revealed that while imiquimod had little effect on interferons expression, its treatment of macrophages resulted in the increased production of the CC chemokines, the natural ligands of the HIV entry co-receptor CCR5, and decreased expression of CD4 and CCR5. These findings are clinically important and indicate that activating the intracellular antiviral immunity by imiquimod has the potential for developing TLR7 agonist-based therapy for HIV infection. The Toll-like receptor (TLR) 7 is a viral sensor for detecting single-stranded ribonucleic acid (ssRNA), the activation of which can induce intracellular innate immunity against viral infections. Imiquimod, a synthetic ligand for TLR7, has been successfully used for the topical treatment of genital/perianal warts in immunocompetent individuals. We studied the effect of imiquimod on the human immunodeficiency virus (HIV) infection of primary human macrophages and demonstrated that the treatment of cells with imiquimod effectively inhibited infection with multiple strains (Bal, YU2, and Jago) of HIV. This anti-HIV activity of imiquimod was the most potent when macrophages were treated prior to infection. Infection of macrophages with pseudotyped HIV NL4-3-ΔEnv-eGFP-Bal showed that imiquimod could block the viral entry. Further mechanistic studies revealed that while imiquimod had little effect on the interferons (IFNs) expression, its treatment of macrophages resulted in the increased production of the CC chemokines (human macrophage inflammatory protein-1 alpha (MIP-1α), MIP-1β, and upon activation regulated normal T cells expressed and secreted (RANTES)), the natural ligands of HIV entry co-receptor CCR5, and decreased the expression of CD4 and CCR5. The addition of the antibodies against the CC chemokines to macrophage cultures could block imiquimod-mediated HIV inhibition. These findings provide experimental evidence to support the notion that TLR7 participates in the intracellular immunity against HIV in macrophages, suggesting the further clinical evaluation of imiquimod for its additional benefit of treating genital/perianal warts in people infected with HIV.
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DOI：
10.4049/jimmunol.0903563
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Akhtar LN;Qin H;Muldowney MT;Yanagisawa LL;Kutsch O;Clements JE;Benveniste EN
通讯作者：
Benveniste EN
影响因子：
3.3
作者：
Hofmann H;Vanwalscappel B;Bloch N;Landau NR
通讯作者：
Landau NR
影响因子：
8.3
作者：
Angelopoulou, Athina;Alexandris, Nikos;Poulas, Konstantinos
通讯作者：
Poulas, Konstantinos
影响因子：
5.4
作者：
Doehle, Brian P.;Hladik, Florian;Gale, Michael, Jr.
通讯作者：
Gale, Michael, Jr.
影响因子：
13.8
作者：
Conant, MA
通讯作者：
Conant, MA