ANTI HIV MOLECULAR THERAPEUTICS TARGETING CHEMOKINE RECEPTORS

针对趋化因子受体的抗 HIV 分子治疗

• 批准号: 6481251
• 负责人: ROGER J POMERANTZ
• 金额: $ 10.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6481251
• 关键词: AIDS dementia complex; HIV infections; Lentivirus; cell line; cell type; chemokine; clinical research; confocal scanning microscopy; cytokine receptors; endoplasmic reticulum; gene expression; gene therapy; human immunodeficiency virus 1; human subject; immunofluorescence technique; immunoglobulin genes; immunoprecipitation; microglia; monoclonal antibody; murine leukemia virus; neuropathology; neurotropic virus; transfection /expression vector; virus replication

Human immunodeficiency virus type I (HIV-1)-induced encephalopathy is an enigmatic syndrome which occurs in a sizable group of patients with AIDS, characterized by cognitive, motor and sensory deficits. The underlying neuropathogenesis of this syndrome remains unclear. Recently, it has been demonstrated that alpha- and beta-chemokine receptors are the major co-receptors for HIV-1, and determine cell- specific viral strain tropism. Initial studies have now demonstrated that chemokine and chemokine receptors are expressed on central nervous system, (CNS)-based cells. As well, alterations in chemokine and chemokine receptor expression in the CNS during HIV-1 infection have also now been reported. As such, chemokine and chemokine receptors may b directly involved with HIV-1induced encephalopathy. We propose to inhibit chemokine receptors in specific CNS-based cells utilizing intracellular immunization approaches and single chain variable fragments (SFvs). Initial studies will develop anti-chemokine receptor SFvs, both human and murine. The CXCR-4, CCR3 chemokine receptors will be the relevant initial molecular targets. After development of human and murine SFVS to the relevant chemokine receptors, these constructs will be tested for their ability to inhibit HIV-1 replication in primary human CNS cell-types. In addition, the effects of altering chemokine interactions with CNS-based cells during HIV-1 infection will be characterized. Both murine leukemia virus vectors and newly designed lentiviral vectors, which transduce non-proliferating cell-types, will be utilized. The molecular mechanisms effects on CNS-based cells (e.g., apoptosis) will be analyzed, based on chemokine receptor intracellular inhibition. These studies will directly interact with several projects within this program and promise to both assist in understanding the neuropathogenesis of HIV-1 infection and move towards our long-term goal of designing relevant and complementary CNS therapeutics in patients with HIV-1 infection.

人类免疫缺陷病毒I型（HIV-1）诱导的脑病是一种神秘的综合征，发生在具有认知，运动和感觉缺陷的特征的大量艾滋病患者中。该综合征的潜在神经病发生尚不清楚。最近，已经证明α-和β-变性受体是HIV-1的主要共受体，并确定细胞特异性病毒菌株对流。最初的研究现已表明，趋化因子和趋化因子受体在中枢神经系统（CNS）基于细胞上表达。同样，HIV-1感染过程中CNS中趋化因子和趋化因子受体表达的改变现已报道。因此，趋化因子和趋化因子受体可能直接与HIV-1-诱导的脑病有关。我们建议利用细胞内免疫方法和单链可变片段（SFV）抑制特定CNS基细胞中的趋化因子受体。 最初的研究将开发人和鼠类的抗化学受体SFV。 CXCR-4，CCR3趋化因子受体将是相关的初始分子靶标。在将人类和鼠SFV开发到相关的趋化因子受体之后，这些构建体将因其抑制原代人CNS细胞类型中HIV-1复制的能力而进行测试。另外，将表征与HIV-1感染期间趋化因子相互作用与基于CNS的细胞相互作用的影响。鼠白血病病毒载体和新设计的慢病毒载体都将被使用非增殖细胞类型。基于趋化因子受体的细胞内抑制，将分析对CNS基细胞（例如凋亡）的分子机制对基于中枢神经系统的细胞的影响（例如，凋亡）。这些研究将直接与该计划中的几个项目相互作用，并承诺既有助于理解HIV-1感染的神经病发生，又要朝着我们在HIV-1感染患者中设计相关和互补的中枢神经系统治疗剂的长期目标。