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 抗人类免疫缺陷病毒（HIV）感染的化疗 和艾滋病的发展。 HIV需要T细胞活化， 用于体外有效复制的胚细胞发生，因此， 诱导T细胞活化和胚细胞生成增强HIV复制。 有证据表明，T细胞活化也是 HIV在体内复制所必需的。 因此， 试图开发一种抑制艾滋病毒复制的策略， 根据这些观察，艾滋病的发展。 脱氢表雄酮（DHEA）是肾上腺分泌的主要产物 在男性和女性中，是哺乳动物葡萄糖-6- 磷酸脱氢酶（G6 PDH）。 DHEA此前已被发现 抑制EB病毒（EBV）诱导的形态学改变， 转化和刺激人外周血DNA合成 血淋巴细胞（PBL）（亨德森等人，致癌作用2：683， 1981年）。 16 α-Br-表雄酮，一种脱氢表雄酮类似物，约为60 作为G6 PDH的抑制剂，其效力比DHEA强两倍， 作为EBV诱导转化的抑制剂更有效。 的 核糖核苷和脱氧核糖核苷逆转1的能力 DHEA的抗增殖和抗分化作用 这强烈表明，抑制核酸合成是一种 DHEA和DHEA的这些生物效应的主要靶点 类似物 在初步实验中，我们发现， DHEA的合成类似物，16 α-氟-5-雄甾烯-17-酮 （8354）和3 β-羟基-16 α-氟-5 α-雄甾烷-17-酮 （羟基8356）抑制PHA处理的PBL中的HIV复制。 HIV复制的抑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， 治疗HIV感染者。 在此，我们建议1） 通过检查DHEA的能力直接测试这一假设， DHEA的合成类似物以抑制对照中的HIV复制， 植物血凝素（PHA）刺激的PBL和连续 增殖T细胞系; 2）测试DHEA的能力， 与3 ′叠氮基-2 ′，3 ′- 双脱氧胸苷（AZT）抑制HIV复制。 DHEA或其 合成类似物具有成为有效辅助剂的潜力 用常规抗病毒化合物治疗HIV 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.