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

已知HIV的生产性感染依赖于 许多细胞因子和过程，特别是那些参与 细胞激活和分化。 虽然代理人， 抑制活化，如环孢菌素，是HIV有效抑制剂 在CD 4 + T细胞中复制，它们显着降低了T细胞的能力， 细胞增殖并对抗原和其他刺激因子产生反应。 信号. MSI-1436及其类似物是新的氨基类固醇， 已知干扰钠/氢交换器（NHE）同种型3， 一种在调节细胞内pH值中起重要作用的细胞反向转运蛋白。 在高浓度下，这些化合物抑制体内和体内的有丝分裂 和离体T细胞，并抑制各种肿瘤的生长， 鼠模型。 发现MSI-1436及其类似物抑制HIV， SIV在体外感染的外周血单个核细胞中的复制 细胞（PBMC），以及减少HIV表达， HIV感染细胞系的浓度不会改变细胞 增殖或活化。 从PBMC中体外分离HIV 从用有丝分裂原刺激的HIV感染供体获得， 回忆抗原被显著抑制，而没有改变 细胞增殖、产生白细胞介素（IL）-2或 表达细胞表面活化抗原。 在体内，MSI-1436是 分析其降低猴免疫缺陷病毒（SIV）的能力 猪尾猕猴慢性SIV感染后的疾病 感染SIV病毒血症没有显著改变;然而， 与对照组相比，治疗组动物的CD 4+：CD 8 + T细胞比率升高。 对照 MSI-1436的最大血液水平的测定揭示了 在这些研究中没有达到有效浓度。 MSI-1436及其类似物对HIV复制影响的分析 和CD 4 + T细胞存活目前正在各种SCID中进行 小鼠模型，包括用人胎儿重组的SCID小鼠 肝/胸腺或人PBL。

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.