CCR5结构与功能研究进展

ＨＩＶ 的侵入与宿主细胞表面共受体ＣＣＲ５ 密切相关。本文报道了ＣＣＲ５ ５端非编码区多态性的研究,以及用基因删除,点突变等方法研究ＣＣＲ５ Ｎ 端和Ｃ端的功能区域。发现了ＣＣＲ５ Δ３２ 受体基因缺陷型能有保护人群免受ＨＩＶ 的感染。     

CCR5及其拮抗剂的研究进展

趋化因子CCR5,作为G蛋白偶联因子超家族(GPCR)成员的细胞膜蛋白,是HIV-1入侵机体细胞的主要辅助受体之一。以CCR5为靶点的HIV-1受体拮抗剂越来越受关注,主要有趋化因子衍生物、非肽类小分子化合物、单克隆抗体、肽类化合物等四类。这些抗病毒活性强、高亲和力的CCR5拮抗剂,已有一部分进入了临床试验阶段。本文对近年来CCR5拮抗剂的相关研究进展进行综述。     

趋化因子受体 CCR5 亲合短肽的筛选

趋化因子受体 5 (CCR5) 是 HIV-1 与宿主细胞结合的辅助因子之一,其功能缺失或被 CCR5 拮抗剂封闭则会阻止 HIV-1 感染细胞 . 为得到与 CCR5 特异结合的肽类拮抗剂,采用噬菌体展示技术,以稳定表达 CCR5 的 CHO 细胞 (CHO/CCR5) 作为靶标,通过噬菌体随机 12 肽库筛选与 CCR5 特异结合的多肽;经过四轮筛选后,挑选 20 个阳性噬菌体克隆进行测序,从中得到 11 个含有 AFDWTFVPSLIL 序列的小分子肽 . 含该序列的噬菌体能与抗人 CCR5 单抗 (2D7) 竞争性结合 CCR5 ,且合成肽 AFDWTFVPSLIL 对趋化因子 RANTES 与 CHO/CCR5 的结合具有明显的抑制作用,初步证明该小肽与 CCR5 具有特异性结合作用 .     

基于修饰CCR5基因的艾滋病基因治疗进展

艾滋病药物治疗主要障碍是难以彻底清除病毒、副作用大、成本高且需长期用药。CCR5是HIV侵染的主要辅助受体,缺陷型CCR5(CCR5△32)的CD4+T细胞对R5嗜性HIV-1病毒感染有高度抵抗力。通过骨髓移植CCR5△32干细胞到患者体内可以降低HIV病毒载量至无法检出水平,同时可维持T细胞数目在正常范围内。但由于CCR5△32基因缺失的人群所占比例少、配型困难等问题,CCR5△32干细胞移植无法广泛用于艾滋病的临床治疗。通过锌指核酸酶(ZFNs)或类转录激活因子效应物核酸酶(TALENs)两种方法可以将自体细胞CCR5基因人为部分缺失,将产生的CCR5缺陷细胞回输体内可阻断HIV-1入侵途径,稳定CD4细胞群体并最终清除病毒。而脐带血干细胞具有对配型要求低等优点,使其作为修饰的靶细胞具有广阔的应用前景。     

CCR5在乙肝病毒感染中有重要作用

<正>在人类中,乙肝病毒(HBV)是最普遍也是主要导致肝病的传染性病原体。之前的调查研究确认了长期乙肝病毒感染的患者不能将HBV完全从肝细胞清除。形成长期感染的主要机制尚未被阐明。然而研究者相信,和能够成功清除HBV感染的患者相比,那些患者基因和免疫参数的不同,可能是长期感染的原因。有研究证明,趋化因子在调节免疫细胞迁移和活化中有重要作用,并在抗HBV的全面免疫应答中是至关重要的。RANTES、MIP-1a和MIP-1b     

CCR5的结构和功能：近两年的研究进展

ＣＣＲ５是趋化蛋白ＭＩＰ－１α,ＭＩＰ－１β、ＲＡＮＴＥＳ的特异性受体,主要表达于单核／巨细胞及Ｔ细胞膜上,具有Ｇ蛋白受体所特有的７个胯膜区。ＣＣＲ５与白细胞的趋经性,炎症反应,嗜Ｍφ型ＨＩＶ－１株对ＣＤ４细胞的感染密度相关。ＣＣＲ５的缺陷与个体对ＨＩＶ－１的抗性有关。本文就近两年在ＣＣＲ５结构特点,转录调控,信号传递,生物学功能等方面的研究进展作一综述。     

Distribution of the CCR5delta32 allele (gene variant CCR5) in Rondônia, Western Amazonian region, Brazil

Since around 1723, on the occasion of its initial colonization by Europeans, Rondonia has received successive waves of immigrants. This has been further swelled by individuals from northeastern Brazil, who began entering at the beginning of the twentieth century. The ethnic composition varies across the state according to the various sites of settlement of each wave of immigrants. We analyzed the frequency of the CCR5Δ32 allele of the CCR5 chemokine receptor, which is considered a Caucasian marker, in five sample sets from the population. Four were collected in Porto Velho, the state capital and the site of several waves of migration. Of these, two, from the Hospital de Base were comprised of HB Mothers and HB Newborns presenting allele frequencies of 3.5% and 3.1%, respectively, a third from the peri-urban neighborhoods of Candelária/Bate-Estaca (1.8%), whereas a fourth, from the Research Center on Tropical Medicine/CEPEM (0.6%), was composed of malaria patients under treament. The fifth sample (3.4%) came from the inland Quilombola village of Pedras Negras. Two homozygous individuals (CCR5Δ32/CCR5Δ32) were detected among the HB Mother samples. The frequency of this allele was heterogeneous and higher where the European inflow was more pronounced. The presence of the allele in Pedras Negras revealed European miscegenation in a community largely comprising Quilombolas.     

CCR5Δ32 Genotypes in a German HIV-1 Seroconverter Cohort and Report of HIV-1 Infection in a CCR5Δ32 Homozygous Individual

Background

Homozygosity (Δ32/Δ32) for the 32 bp deletion in the chemokine receptor 5 (CCR5) gene is associated with strong resistance against HIV infection. Heterozygosity is associated with protection of HIV-1 disease progression.

Methodology/Principal Findings

We genotyped a population of 737 HIV-positive adults and 463 healthy controls for the CCR5Δ32 deletion and found heterozygous frequencies of 16.2% (HIV-negative) and 17.5% (HIV-positive) among Caucasian individuals. Analysis of CCR5Δ32 influence on disease progression showed notably lower viral setpoints and a longer time to a CD4 count of <200 µl⁻¹ in seroconverters heterozygous for the deletion. Furthermore, we identified one HIV-positive man homozygous for the Δ32 deletion.

Conclusions/Significance

The protective effect of CCR5 Δ32 heterozygosity is confimed in a large cohort of German seroconverters. The HIV-infected CCR5 Δ32 homozygous individual, however, displays extremely rapid disease progression. This is the 12th case of HIV-infection in this genotype described worldwide.     

CCL5/CCR5生物学轴在肿瘤中作用的研究进展

肿瘤因其易转移、易复发的特性成为一大难以治愈的疾病,已严重威胁到人类的生命健康。肿瘤微环境在肿瘤的生长、迁移、免疫逃逸、血管生成等过程中具有明显的促进作用。肿瘤微环境中细胞分泌的CCL5发挥的作用已受到越来越多的关注,且许多研究表明抑制CCL5/CCR5生物学轴可抑制肿瘤迁移、血管生成等,预示着这可能成为一个新的肿瘤治疗策略。本文总结了近年来关于CCL5/CCR5生物学轴的研究,包括CCL5/CCR5生物学轴介导的肿瘤生长迁移、血管生成、免疫逃逸等作用,及CCR5抑制剂在肿瘤治疗中的广阔前景。     

Primary acute dengue and the deletion in chemokine receptor 5 (CCR5Δ32)

Dengue virus is a significant arboviral pathogen that is continuing to spread due to human travel and invasion of the mosquito vectors into new regions. Chemokine receptor 5 (CCR5) has a truncated 32 base pair deletion form (CCR5Δ32), which has been associated with resistance to HIV but increased severity in some flaviviral diseases. If CCR5Δ32 is associated with dengue, European carriers of this mutation may be at increased risk. In a Western Australian population with the same frequency of CCR5Δ32 (0.08) as that found in southern Europe there was no significant difference in CCR5Δ32 allele frequency between returned travellers with and without dengue (p = 0.82, OR = 0.86, 95% CI = 0.35–2.1).     

基于调控趋化性细胞因子受体CCR5抗HIV-1的研究进展

获得性免疫缺陷综合征(AIDS),又称"艾滋病",是威胁着人类生命健康的重大传染性疾病。趋化性细胞因子受体5(Chemotactic cytokine receptor 5,CCR5)作为嗜巨噬细胞性1型人类免疫缺陷病毒(Human immunodeficiency virus type 1,HIV-1)进入宿主细胞的必需的辅助受体自发现以来被广泛关注。CCR5在HIV靶细胞表面的表达水平与靶细胞的病毒载量呈正相关且和艾滋病的进程强相关。因此,通过干预CCR5在靶细胞表面的表达能在一定程度上阻止HIV进入靶细胞。因此,本文从分子水平阐述干预CCR5的主要生物学机制,并对近几年的研究进行综述。     

CCR5 in T cell-mediated liver diseases: what's going on?

The chemokine receptor CCR5 came into worldwide prominence a decade ago when it was identified as one of the major coreceptors for HIV infectivity. However, subsequent studies suggested an important modulatory role for CCR5 in the inflammatory response. Specifically, CCR5 has been reported to directly regulate T cell function in autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Moreover, T cell-mediated immune responses are proposed to be critical in the pathogenesis of autoimmune and viral liver diseases, and recent clinical and experimental studies have also implicated CCR5 in the pathogenesis of autoimmune and viral liver diseases. Therefore, in this brief review, we highlight the evidence that supports an important role of CCR5 in the pathophysiology of T cell-mediated liver diseases with specific emphasis on autoimmune and viral liver diseases.     

What is the future of CCR5 antagonists in rheumatoid arthritis?

A clinical trial of lupus patients with nephritis was established to determine any possible role for Atacicept, a biologic drug that blocks two B-cell-activating factors (BLyS and APRIL). The trial was stopped after just six patients had been enrolled because three patients developed serious infections. Initial concerns that the biologic was the main cause of the increased susceptibility to these infections have had to be revised on close inspection of the data. The evidence clearly points to a previously unrecognised capacity for mycophenolate to cause notable drops in immunoglobulin levels as the prime suspect.     

Structural insight into the binding complex: β-arrestin/CCR5 complex

The chemokine receptor 5 (CCR5) belongs to the superfamily of serpentine G protein-coupled receptors (GPCRs). The DRY motif (Asp, Arg, Tyr) of the intracellular loop 2 (ICL2), which is highly conserved in the GPCRs has been shown to be essential for the stability of folding of CCR5 and the interaction with β-arrestin. But the molecular mechanism by which it recognizes and interacts with β-arrestin has not been elucidated. In the present study, we described the active state of the β-arrestin structure using normal mode analysis and characterized the binding cleft of CCR5-ICL2 with β-arrestin using SABRE© docking tool and molecular dynamics simulation. Based on our computational results, we proposed a mode of binding between the ICL2 loop of CCR5 and β-arrestin structure, and modeled the energetically stable β-arrestin/CCR5 complex. In view of CCR5’s importance as a therapeutic target for the treatment of HIV, this observation provides novel insight into the β-arrestin/CCR5 pathway. As a result, the current computational study of the detailed β-arrestin/CCR5 binding complex could provide the rationale for the development of next generation of HIV peptide inhibitors as therapeutic agents.     

小鼠CCR5基因在活体内表达受迟发型超敏反应的调节

趋化因子(chemokine)在机体的免疫监视和慢性炎症反应中起着重要作用。β-趋化因子受体5(CCR5)是巨噬细胞嗜性(M-tropic)HIV-1进入靶细胞的一个重要辅助因子。作用在成功克隆一新的趋化因子受体5(muCCR5)中研究了该基因在小鼠活体内的表达。结果表明,muCCR5 cDNA全长2888 bp,ORF为     

CCR5基因转染对骨髓源神经干细胞生物学行为的影响

骨髓源神经千细胞（bonemarrow—derived neural stem cells,BM—NSCs）具有自我更新和分化为神经元与神经胶质细胞的潜能,可用于修复治疗多种神经系统退变与损伤性疾病。但由于其表面缺乏趋化因子受体,移植后向中枢病变部位迁移的速度较慢,疗效欠佳。该研究构建了趋化因子受体CCR5基因,并转染BM—NSCs,用免疫荧光细胞化学法、流式细胞胞仪法及Boyden小室细胞趋化实验,体外研究了CCR5高表达对BM-NSCs增殖、分化与迁移能力的影响。结果表明,CCR5高表达能显著增强BM．NSCs~O趋化能力,而不影响其自我更新和分化为神经元与神经胶质细胞的能力,说明其植入体内后可保持细胞替代与神经修复作用,并能快速大量迁移到病灶部位,显著增强疗效。