The spreading of HIV-1 infection in the human organism is caused by fractalkine trafficking of the infected lymphocytes - a review, hypothesis and implications for treatment
The spreading of HIV-1 infection in the human organism is caused by fractalkine trafficking of the infected lymphocytes - a review, hypothesis and implications for treatment
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DOI：
10.1007/s11262-006-0056-x
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发表时间：
2007-04-01
期刊：
影响因子：
1.6
通讯作者：
Becker, Yechiel
中科院分区：
文献类型：
--
作者：
Becker, Yechiel
关于HIV-1/AIDS的综述[1-8]强调了HIV-1病毒粒子利用树突状细胞（dc）从生殖器（病毒感染的门户）运输到引流淋巴结的机制，树突状细胞携带HIV-1病毒粒子，并通过HLA I类和II类向CD4(+) T细胞呈递病毒抗原。T细胞与HLAⅱ类分子呈递的病毒抗原相互作用，使其成为Th2细胞，成为HIV-1感染的靶点和HIV-1子代病毒粒子的产生者。与HLA I类递呈的病毒抗原相互作用的T细胞极化为Th1细胞，Th1细胞刺激CD8(+) T细胞前体发育为抗病毒细胞毒性T细胞。此外，HIV-1病毒粒子释放gp120糖蛋白分子，与FC epsilon RI+先天系统细胞（嗜碱性细胞、肥大细胞和单核细胞）结合的IgE免疫球蛋白分子结合，诱导它们释放大量Th2细胞因子（IL-4、IL-5、IL-10、IL-13），从而产生类似过敏的情况。本综述试图明确趋化因子受体如CCR5和CXCR4，特别是fractalkine受体CX3CR1在健康个体和HIV-1/AIDS患者淋巴细胞运输中的作用。趋化因子受体作为HIV-1病毒粒子gp120糖蛋白共受体的作用已经被明确，但fractalkine和fractalkine受体的作用直到最近才被阐明[9-19]。在健康个体中，fractalkine通过血管内皮细胞表达，CX3CR1受体在白细胞上表达，白细胞沿fractalkine浓度升高的方向在外周血中迁移。在HIV-1/艾滋病患者中，病毒感染的CD4(+) Th2细胞迁移到胸腺、生殖器、胃肠道和大脑中含有适应性免疫系统细胞的器官。Faure及其合作者最近报道了一项最重要的发现，揭示了人类CX3CR1基因表达对艾滋病感染进展的重要性[20,21]，他们发现，在hiv -1感染的个体中，遗传了一个fractalkine受体基因的多态性V249I或T280M，分别位于CX3CR1蛋白的第6和第7跨膜结构域，从而影响了艾滋病的延迟或快速进展。CX3CR1基因的T280M突变导致艾滋病的快速进展，而V249I突变患者的艾滋病进展要慢得多。这些研究表明，通过使用fractalkine拮抗剂治疗HIV-1患者，可能会减缓或阻止HIV-1/艾滋病的进展，这种拮抗剂可以结合并抑制fractalkine受体的活性。假设fractalkine拮抗剂、IL-4拮抗剂IL-4 δ 2和佐剂CpG ODN联合治疗HIV-1/AIDS患者诱导I型IFN从PDF中释放，并可能抑制HIV-1感染，特别是在haart治疗的感染耐药HIV-1突变体的患者中，因为预防了病毒逃避免疫应答所需的免疫细胞的可用性。这一假设表明，建议的HIV-1感染者治疗模式的优势在于预防病毒蛋白引起免疫缺陷的细胞过程，以及在不诱导耐药突变体的情况下预防HIV-1复制。
The reviews on HIV-1/AIDS [1-8] highlighted the mechanism by which HIV-1 virions utilize dendritic cells (DCs) for transport from the genitals, the portal of virus infection, to the draining lymph nodes where DCs carry HIV-1 virions and present viral antigens by HLA class I and II to CD4(+) T cells. Interaction of the T cells with viral antigens presented by HLA class II molecules polarizes them to become Th2 cells, the targets of HIV-1 infection and producers of HIV-1 progeny virions. The T cells which interact with viral antigen presented by HLA class I polarize to become Th1 cells, which stimulate the CD8(+) T cell precursors to develop into antiviral cytotoxic T cells. In addition, HIV-1 virions shed gp120 glycoprotein molecules which bind to IgE immunoglobulin molecules bound to FC epsilon RI+ innate system cells (basophils, mast cells and monocytes) and induce them to release large amounts of Th2 cytokines (IL-4, IL-5, IL-10, IL-13), thereby creating an allergy-like condition. The present review attempts to define the role of chemokine receptors like CCR5 and CXCR4, and especially fractalkine receptor CX3CR1 in the trafficking of lymphocytes in healthy individuals and HIV-1/AIDS patients. The role of chemokine receptors as co-receptors for HIV-1 virion gp120 glycoprotein has been defined, but the role of fractalkine and fractalkine receptor has been clarified only recently [9-19]. In healthy individuals fractalkine is expressed by blood vessel endothelial cells and the CX3CR1 receptors are expressed on leukocytes that migrate in the peripheral blood in the direction of increased fractalkine concentration. In HIV-1/AIDS patients the virus-infected CD4(+) Th2 cells migrate to organs that harbor the adaptive immune system cells in the thymus, genitals, gastrointestinal tract, and to the brain. A most significant finding which revealed the importance of the human CX3CR1 gene expression to the progression of the infection to the stage of AIDS was recently reported by Faure and collaborators [20, 21] who showed that the delayed or rapid progression to AIDS was affected in HIV-1-infected individuals who had inherited a fractalkine receptor gene with the polymorphisms V249I or T280M, respectively, located in the sixth and seventh transmembrane domains of CX3CR1 protein. The T280M mutation in the CX3CR1 gene caused a rapid progression to AIDS, while in patients with the V249I mutation progression to AIDS was much slower. These studies led to the idea that it might be possible to slow or prevent HIV-1/AIDS progression in HIV-1 patients by treating them with fractalkine antagonists that will bind to and inhibit the activity of the fractalkine receptor. It is hypothesized that treatment of HIV-1/AIDS patients with a combination of fractalkine antagonists, IL-4 antagonist IL-4 delta 2 and the adjuvant CpG ODN induced release of type I IFN from PDF, and may inhibit HIV-1 infection, especially in HAART-treated patients infected with drug-resistant HIV-1 mutants due to prevention of the availability of immune cells needed for the viral evasion of the immune response. The hypothesis implies that the advantage of the suggested mode of treatment of HIV-1-infected people is prevention of cellular processes that are used by the viral protein to cause immunodeficiency, and prevention of HIV-1 replication without induction of resistant mutants.