Insights into HIV chemotherapy.
Insights into HIV chemotherapy.
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DOI：
10.1089/aid.1992.8.963
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发表时间：
1992-06
影响因子：
1.5
通讯作者：
Raymond F. Schinazi;Jan R. Mead;P. M. Feorino
中科院分区：
文献类型：
--
作者：
Raymond F. Schinazi;Jan R. Mead;P. M. Feorino
在过去的十年中，获得性免疫缺陷综合征(AIDS)已经从一种未知原因的致命医学好奇演变为一种新的病毒性疾病的主要流行。1艾滋病的一个方面在这一演变过程中没有改变--它仍然是致命的。在高发地区，其社会和经济影响是巨大的。1991年底，美国疾病控制中心报告了20多万例艾滋病病例。因此，迫切需要开发有效、安全、抗病毒的药物来抑制人类免疫缺陷病毒1型(HIV-1；HIV)的复制，防止疾病的进展，并治疗患有艾滋病或艾滋病相关复合体(ARC)的患者。2艾滋病的病原体艾滋病毒生物合成的任何步骤都容易受到抗病毒干预的攻击。3‘4这些靶点中最突出的是病毒编码的逆转录酶(RT)，而最难以捉摸的是整合的病毒基因。多中心安慰剂对照研究证实了3‘-叠氮-3’-脱氧胸苷(AZT，齐多夫定)治疗艾滋病的临床疗效，为开发更有效和/或毒性更低的化合物铺平了道路。人们对抑制病毒逆转录酶以外的靶点的非核苷化合物将被证明更有效抱有很大的期望。然而，基因工程形式的各种蛋白质，特别是可溶性CD_4，一种干扰病毒gp20与淋巴细胞上的CD_4受体结合的分子，已被证明对野生型病毒的活性范围很窄，迄今未能控制人类的艾滋病毒感染。6·7目前正在对各种CD4抗体杂化分子进行评估。然而，控制这种病毒感染似乎是一项艰巨的任务，因为我们正在处理各种类型的细胞，它们急性、长期和潜伏地携带病毒。现代抗病毒化疗将不得不针对这些不同的感染细胞。有必要找到能够抑制或抑制HIV-1在人类体内传播的化合物或联合疗法。我们假设，HIV感染可以通过安全有效的药物来控制，这些药物对这些不同类型的感染细胞起协同作用。对HIV-1建立和维持潜伏期的机制以及导致潜伏病毒重新激活的因素的研究是至关重要的。目前对这些问题的研究将有助于我们开发更有效和更具体的化合物。此外，用于预测新制剂在人体内的活性和毒性的改进的分析或动物模型也是必要的。这篇批判性的综述集中在正在开发的一些更有前景的化合物上，这些化合物正在开发用于治疗HIV-1感染。它的目的并不是要详尽地讨论这个问题。意义重大的是，在过去的五年里，科学界团结起来，开发了多种潜在的治疗方法。这种反应导致了几种核苷类和非核苷类抗病毒药物已被批准或即将获得批准用于临床试验。关于这些化合物的安全性和有效性的信息将成为开发更多的抗病毒药物以预防和治疗这种毁灭性疾病的基础。
INTHE LAST DECADE, acquired immunodeficiency syndrome (AIDS) has evolved from a deadly medical curiosity of unknown cause into a major epidemic of a new viral disease. 1 One aspect of AIDS has not changed during that evolution—it remains fatal. In high-incidence areas, the social and economic impact has beensubstantial. At the endof 1991, more than 200,000 cases of AIDS in the United States have been reported to the Centers for Disease Control. Thus, it is imperative to develop effective, safe, antiviral drugs to suppress human immunodeficiency virus type 1 (HIV-1; HIV) replication, pre¬ vent the progression of disease, and treat individuals with AIDS or AIDS-related complex (ARC). 2 Any step in the biosynthesis of HIV, the causative agent of AIDS, is susceptible to attack by antiviral intervention. 3'4 The most prominent of these targets is the virus-coded reverse transcriptase (RT), and the most elusive is the integrated virogene. Multicentered placebo-controlled studies demonstrating the clinical efficacy of 3'-azido-3'-deoxythymidine (AZT, zidovu¬ dine) for the treatment of AIDS have paved the way for the development of more potent and/or less toxic compounds. 5 There are great expectations that non-nucleoside compounds that inhibit targets other than the viral RT will prove to be more effective. However, genetically engineered forms of various proteins, particularly soluble CD4, a molecule that interferes with the binding of the viral gpl20 to CD4 receptors on lymphocytes, have been shown to have a narrow spectrum of activity against wild-type virus and so far have failed to control HIV infection in humans. 6· 7 Various CD4-antibody hybrid molecules currently are being evaluated. 8 However, controlling this virus infection appears to be a formidable task since we are dealing with a variety of cell types which harbor virus acutely, chronically, and latently. Modern antiviral chemotherapy will have to target these different infected cells. It is necessary to find compounds or combined modalities that will suppress or inhibit the spread of HIV-1 in humans. We hypothesize that HIV infection can be controlled by safe and effective drugs that act in concert on these various types of infected cells. Studies on the mechanism by which HIV-1 establishes and maintains latency, and factors that cause reactivation of latent virus are of critical interest. Current research on these problems will assist us in developing more potent and specific compounds. In addition, improved assays or animal models for predicting activity and toxicity of new agents in humans also are necessary. The critical review focuses on some of the more promising compounds that are being developed to treat HIV-1 infections. It is not meant to cover the subject exhaustively. Of significance is that over the last five years the scientific community has rallied to develop a multitude ofpotential treatments. This response has resulted in several nucleosides and non-nucleoside antivirals that have been approvedor are close to approval for clinical trials in humans. The information on the safety and efficacy of these compounds will form the foundation for the development of additional antiviral agents for the prevention and treatment of this devastating disease.