Inhibition of 3'azido-3'deoxythymidine-resistant HIV-1 infection by dehydroepiandrosterone in vitro.
Inhibition of 3'azido-3'deoxythymidine-resistant HIV-1 infection by dehydroepiandrosterone in vitro.
复制标题
体外脱氢表雄酮抑制 3叠氮基-3脱氧胸苷耐药 HIV-1 感染。
DOI：
10.1006/bbrc.1994.1862
复制
发表时间：
1994
影响因子：
3.1
通讯作者：
Henderson,EE
中科院分区：
文献类型：
--
作者：
Yang,JY;Schwartz,A;Henderson,EE
从获得性免疫缺陷综合征 (AIDS) 患者中分离出的 1 型人类免疫缺陷病毒 (HIV-1) 在治疗一两年后显示出对 3'叠氮-3'脱氧胸苷 (AZT) 的耐药性。 AZT还具有显着的毒副作用，进一步限制了其在治疗HIV-1感染者中的使用。脱氢表雄酮 (DHEA) 已被证明具有广泛的生物功能，可口服生物利用并且相对无毒。流行病学研究提供的证据表明，血清 DHEA 水平降低与 HIV-1 感染中的 AIDS 进展有关。 DHEA 还被证明可以在体外抑制 HIV-1 复制，并阻止慢性感染细胞系中的 HIV-1 重新激活。然而，目前还没有关于 DHEA 抑制 AZT 抗性 HIV-1 菌株复制能力的报道。我们研究了 DHEA 治疗是否可以抑制 AZT 抗性 HIV-1 菌株的复制。在感染了 AZT 敏感或 AZT 抗性 HIV-1 分离株的 MT-2 细胞培养物中添加 DHEA，可导致剂量依赖性抑制 HTV-1 诱导的细胞病变效应，并抑制 HIV-1 复制（通过逆转录酶活性的积累来测量）。根据细胞病变效应和逆转录酶活性的积累测量，浓度低至 50 μM 时，DHEA 可使 AZT 抗性 HIV-1 复制减少 50% 以上。这项研究提供的证据表明 DHEA 可以抑制 AZT 抗性以及野生型 HIV-1 的复制。由于 DHEA 的主要靶标是导致 HIV-1 复制激活的代谢和细胞信号传导途径，因此 DHEA 应能有效对抗 HIV-1 的多重耐药菌株。结合最近发现的免疫调节特性，DHEA 能够抑制野生型和 AZT 抗性 HIV-1 复制的发现表明，体内 DHEA 的作用范围可能比最初预期的要广得多。
Human immunodeficiency virus type 1 (HIV-1) isolated from patients with acquired immunodeficiency syndrome (AIDS) shows resistance to 3′azido-3′deoxythymidine (AZT) after one or two years of treatment. AZT also has significant toxic side effects, further limiting its use in the therapy of HIV-l-infected individuals. Dehydroepiandrosterone (DHEA) has been shown to have a broad spectrum of biological functions, to be bioavailable orally and to be relatively nontoxic. Epidemiological studies provide evidence that reduced serum levels of DHEA are related to the progression of AIDS in HIV-1 infection. DHEA has also been shown to inhibit HIV-1 replication in vitro and block HIV-1 reactivation from chronically infected cell lines. However, there have been no reports on the ability of DHEA to inhibit the replication of AZT-resistant strains of HIV-1. We investigated whether DHEA treatment could inhibit replication of AZT-resistant strains of HIV-1. Addition of DHEA to MT-2 cell cultures infected with either AZT-sensitive or AZT-resistant isolates of HIV-1 resulted in dose-dependent inhibition of HTV-1-induced cytopathic effect and suppression of HIV-1 replication as measured by accumulation of reverse transcriptase activity. At a concentration as low as 50 μM, DHEA reduced AZT-resistant HIV-1 replication over 50 percent as measured by cytopathic effect and accumulation of reverse transcriptase activity. This study provides evidence that DHEA can inhibit the replication of AZT-resistant as well as wild-type HIV-1. Since the main targets for DHEA are metabolic and cellular signaling pathways leading to HIV-1 replication-activation, DHEA should be effective against multidrug-resistant strains of HIV-1. Combined with recently discovered immunoregulatory properites, the finding that DHEA is able to inhibit replication of both wild-type and AZT-resistant HIV-1 suggests that in vivo DHEA may have a much broader spectrum of action than originally anticipated.