A Novel Anti-HIV Activity of CCR6 via APOBEC3G: Relevance to CNS Infection

摘要：我们已经证明，当防御蛋白hBD2和趋化因子MIP-31 （CCL20）结合到它们的细胞受体CCR6上时，它们会诱导细胞内抗HIV病毒的抗病毒活性，这种活性在不表达CCR6的细胞中是不存在的。虽然包括HIV在内的包膜病毒的直接失活已被认为是防御素的一种机制，但据我们所知，通过CCR6介导的HIV抑制是一种新的机制。这种机制发生在细胞进入后，但在逆转录时或之前，似乎是由于细胞内抗病毒蛋白APOBEC3G的表达增加。百日咳毒素消除了抑制作用，提示g1依赖性信号转导的参与。CCR6在与HIV感染高度相关的细胞上表达；它们包括记忆T细胞、树突状细胞、活化巨噬细胞、小胶质细胞和Th17细胞。与CCR6结合的防御素主要由上皮细胞和星形胶质细胞表达，而MIP-31则由粘膜上皮细胞、活化的外周血单核细胞和星形胶质细胞产生。由于CCR6及其配体均在与HIV感染高度相关的中枢神经系统细胞中表达，因此针对CCR6的HIV抑制机制可能在控制HIV感染和中枢神经系统症状中发挥关键作用。此外，阐明细胞内通路和受CCR6激活限制的HIV生命周期中的步骤可以为感染早期病毒-宿主相互作用提供见解，并确定抗病毒治疗的新靶点。我们建议在原代细胞中鉴定APOBEC3G作为CCR6介导的抗病毒活性的效应分子；证明CCR6诱导的信号转导增加APOBEC3G的表达，并确定什么是关键的特异性途径；证明ccr6介导的HIV抑制对原发和非b病毒分离物的广谱有效性；检测CCR6、CCR6配体、APOBEC3G在临床标本中的表达。

DESCRIPTION (provided by applicant): A novel anti-HIV activity of CCR6 via APOBEC3G: relevance to CNS infection Abstract We have shown that when defensin hBD2 and chemokine MIP-31 (CCL20) bind to their cellular receptor, CCR6, they induce an intracellular antiviral activity against HIV that is absent in cells that do not express CCR6. While direct inactivation of enveloped viruses including HIV has been implicated as one mechanism of defensins, to our knowledge, HIV inhibition mediated through CCR6 is novel. The mechanism occurs post entry but at or before reverse transcription, and appears to be due to increased expression of the intracellular antiviral protein APOBEC3G. Inhibition is abrogated by pertussis toxin, suggesting the involvement of G1i-dependent signal transduction. CCR6 is expressed on cells that are highly relevant to HIV infection; they include memory T cells, dendritic cells, activated macrophages, microglia and Th17 cells. Defensins that bind to CCR6 are primarily expressed by epithelial cells and astrocytes, while MIP-31 is produced by mucosal epithelial cells, activated peripheral blood mononuclear cells and astrocytes. Since both CCR6 and its ligands are expressed in the central nervous system in cells highly relevant to HIV infection, an HIV suppressive mechanism that targets CCR6 may play a critical role in controlling HIV infection and CNS symptoms. Further, elucidation of the intracellular pathways and the step(s) in the HIV life-cycle limited by CCR6 activation could provide insights into virus-host interactions early in infection and identify new targets for antiviral therapy. We propose to identify APOBEC3G as the effector molecule of the antiviral activity mediated by CCR6 in primary cells; to demonstrate that CCR6- induced signal transduction increases APOBEC3G expression and identify what is the critical specific pathway; to demonstrate the efficacy of CCR6-mediated HIV inhibition on a broad spectrum of primary and non-B viral isolates; and to measure the expression of CCR6, CCR6 ligands, and APOBEC3G in clinical specimens. PUBLIC HEALTH RELEVANCE: The studies proposed here will investigate the mechanism of inhibition of HIV by a cellular receptor called CCR6. These studies are highly relevant to prevention and treatment of HIV infection because they will contribute knowledge that can be used to develop novel anti-HIV drugs that will target CCR6.