REGULATION OF HIV REPLICATION BY NOVEL AMINOSTEROLS, MSI-1436 AND ITS ANALOGS

新型氨基甾醇 MSI-1436 及其类似物对 HIV 复制的调节

• 批准号: 6160766
• 负责人: A KINTER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160766
• 关键词: Macaca nemestrina; SCID mouse; antiAIDS agent; antimetabolites; antiport; antiviral agents; cell growth regulation; cell line; cell proliferation; drug design /synthesis /production; drug screening /evaluation; helper T lymphocyte; human immunodeficiency virus; human tissue; inhibitor /antagonist; membrane transport proteins; monocyte; nonhuman therapy evaluation; simian immunodeficiency virus; sterols; tissue /cell culture; virus replication

Kinter Productive infection by HIV is known to be dependent upon numerous cellular factors and processes, particularly those involved in cellular activation and differentiation. While agents which broadly inhibit activation, such as cyclosporin, are potent suppressers of HIV replication in CD4+ T cells, they dramatically reduce the ability of T cells to proliferate and respond to antigens and other stimulatory signals. MSI-1436 and its analogs are novel aminosterols which are known to interfere with the sodium/hydrogen exchanger (NHE) isoform 3, a cellular antiporter important in the regulation of intracellular pH. At high concentrations these compounds suppress mitogenesis both in vivo and ex vivo in T cells and suppress the growth of various tumors in murine models. MSI-1436 and its analogs were found to suppress HIV and SIV replication from in vitro infected peripheral blood mononuclear cells (PBMCs) as well as to reduce HIV expression in chronically HIV-infected cell lines at concentrations which did not alter cellular proliferation or activation. In vitro isolation of HIV from PBMC obtained from HIV-infected donors that were stimulated with mitogens or recall antigens was significantly inhibited without alteration in the ability of the cells to proliferate, produce interleukin (IL)-2 or express cell surface activation antigens. In vivo, MSI-1436 was analyzed for its ability to reduce simian immunodeficiency virus (SIV) disease in pigtail macaques following establishment of chronic SIV infection. SIV viremia was not significantly altered; however, the CD4+:CD8+ T cells ratios were elevated in treated animals compared to controls. Determination of maximal blood levels of MSI-1436 revealed that efficacious concentrations were not achieved in these studies. Analyses of the effect of MSI-1436 and its analogs on HIV replication and CD4+ T-cell survival are presently being conducted in various SCID mouse models including SCID mice reconstituted with human fetal liver/thymus or with human PBL.

已知由艾滋病毒引起的多发性感染依赖于 大量的细胞因子和过程，特别是那些参与 细胞的激活和分化。而代理商大体上是 抑制激活，如环孢菌素，是艾滋病毒的有效抑制剂 在CD4+T细胞中复制，它们会显著降低T细胞的能力 细胞增殖并对抗原和其他刺激物做出反应 信号。MSI-1436及其类似物是一种新型的氨基甾醇 已知干扰钠/氢交换器(NHE)亚型3， 一种细胞反向转运蛋白，在调节细胞内的pH方面很重要。 在高浓度时，这些化合物抑制体内的有丝分裂 和体外T细胞并抑制多种肿瘤的生长 小鼠模型。MSI-1436及其类似物被发现能抑制HIV和 从体外感染的外周血单核细胞中复制SIV 细胞(PBMC)以及减少慢性艾滋病病毒的表达 HIV感染细胞株的浓度不会改变细胞 增殖或激活。人外周血单核细胞中HIV的体外分离 从感染艾滋病毒的捐赠者那里获得的，这些捐赠者被有丝分裂原刺激或 在没有改变的情况下，召回抗原被显著抑制 细胞增殖、产生白介素2或 表达细胞表面活化抗原。在体内，MSI-1436是 对其降低猴免疫缺陷病毒(SIV)能力的分析 猪尾猕猴慢性SIV建立后的疾病 感染。SIV病毒血症没有明显改变；然而， 与对照组相比，治疗组小鼠的CD4+/CD8+T细胞比率升高 控制。MSI-1436最大血药浓度测定显示 在这些研究中没有达到有效的浓度。 MSI-1436及其类似物对HIV复制的影响分析 目前在不同的SCID中正在进行CD4+T细胞的存活 包括人胚胎重组的SCID小鼠在内的小鼠模型 肝/胸腺或人外周血淋巴细胞。