INHIBITION OF HIV REPLICATION BY DHEA AND ITS ANALOGS

虽然已经取得了进展，但我们仍然缺乏一个真正有效的 针对人类免疫缺陷病毒(HIV)感染的化疗 并逐渐发展为艾滋病。HIV需要T细胞激活和 在体外有效复制的胚泡发生，因此 诱导T细胞活化和转化促进HIV复制。 有证据表明，T细胞的激活也是 艾滋病毒在体内复制所需的。因此，我们有了 试图制定一种策略来抑制艾滋病毒复制和 基于这些观察，进展为艾滋病。 脱氢表雄酮(DHEA)，肾上腺主要分泌产物 对男性和女性来说，是一种有效的哺乳动物葡萄糖-6抑制剂- 磷酸脱氢酶(G6PDH)。此前已发现脱氢表雄酮 抑制EB病毒(EBV)诱导的形态学改变 人外周血中DNA合成的转化和刺激 血淋巴细胞(PBL)(Henderson等人，癌变2：683， (1981年)。16α-溴-表雄酮，一种脱氢表雄酮类似物，约为60 作为G6PDH的抑制剂，DHEA的效力是DHEA的三倍 更有效地抑制EBV诱导的转化。这个 核糖核苷和脱氧核糖核苷的1逆转能力 脱氢表雄酮的抗增殖和抗分化作用 强烈表明抑制核酸合成是一种 脱氢表雄酮和脱氢表雄酮生物效应的主要靶点 类比。在初步实验中，我们发现了那本小说 脱氢表雄酮的合成类似物16α-氟-5-雄酮-17-酮 (8354)和3β-羟基-16α-氟-5α-雄烷-17-酮 (羟基8356)抑制PHA处理的PBL中的HIV复制。 抑制HIV复制不是由于这些化合物的细胞毒性 化合物。由于DHEA及其类似物相对无毒， 它们代表了一类新的化合物，具有潜在的 艾滋病毒感染者的治疗。在此，我们建议1) 通过检查DHEA和DHEA的能力直接检验这一假设 DHEA的合成类似物在对照组和对照组中抑制HIV复制 植物血凝素(PHA)刺激的外周血淋巴细胞并持续 体外扩增T细胞；2)检测脱氢表雄酮(DHEA)和 合成类似物与3‘叠氮-2’，3‘- 二脱氧胸苷(AZT)在抑制HIV复制中的作用。DHEA或ITS 合成类似物有可能成为一种有效的辅助工具 常规抗病毒药物治疗HIV的研究进展 感染。

Although progress has been made, we still lack a truly efficient chemotherapy against human immunodeficiency virus (HIV) infection and progression towards AIDS. HIV requires T cell activation and blastogenesis for efficient replication in vitro, thus agents which induce T cell activation and blastogenesis enhance HIV replication. There is evidence to suggest that T cell activation is also required for HIV replication in vivo. Consequently we have attempted to develop a strategy to inhibit HIV replication and progression to AIDS based on these observations. Dehydroepiandrosterone (DHEA), a major adrenal secretory product in men and women, is a potent inhibitor of mammalian glucose-6- phosphate dehydrogenase (G6PDH). DHEA has previously been found to suppress Epstein-Barr virus (EBV)-induced morphologic transformation and stimulation of DNA synthesis in human peripheral blood lymphocytes (PBLs) (Henderson et al., Carcinogenesis 2:683, 1981). 16 alpha-Br-epiandrosterone, a DHEA analog, is about 60 times more potent than DHEA as an inhibitor of G6PDH, and is much more effective as an inhibitor of EBV-induced transformation. The ability of ribonucleosides and deoxyribonucleosides to 1 reverse the anti-proliferative and anti-differentiating effects of DHEA strongly suggests that inhibition of nucleic acid synthesis is a primary target for these biological effects of DHEA and DHEA analogs. In preliminary experiments we have found that novel synthetic analogs of DHEA, 16 alpha-fluoro-5-androsten-17-one (8354) and 3 beta-hydroxy-16 alpha-fluoro-5 alpha-androstan-17-one (hydroxy 8356) inhibit HIV replication in PHA-treated PBLs. Inhibition of HIV replication was not due to cell toxicity of these compounds. Since DHEA and its analogs are relatively nontoxic, they represent a novel class of compounds with potential for therapy of HIV-infected individuals. Here we propose 1) to directly test this hypothesis by examining the ability of DHEA and synthetic analogs of DHEA to inhibit HIV replication in control and phytohemagglutin (PHA)-stimulated PBLs and continuously proliferating T cell lines; 2) test the ability of DHEA and synthetic analogs to act synergistically with 3'azido-2',3'- dideoxythymidine (AZT) in inhibiting HIV replication. DHEA or its synthetic analogs has the potential of being an efficient adjunct therapy with conventional antiviral compounds in treating HIV infection.