Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Medicina. Avda. de Menéndez Pidal s/n, Universidad de Córdoba, Córdoba, Spain.
Curr Drug Targets. 2011 Mar 1;12(3):348-56. doi: 10.2174/138945011794815266.
The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication in patients treated with highly active antiretroviral therapy. The molecular mechanisms by which integrated HIV-1 is repressed during latency have been partially identified in different models of HIV-1 latency, and the involvement of multiple processes has been demonstrated. Therefore, several molecular targets amenable to pharmacological manipulation have emerged to antagonize HIV-1 latency in the viral reservoirs. In this context, it has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. HIV-1 reactivation therapy is a potential therapeutic option to purge the viral reservoirs. The goal of this therapy is to enhance the transcriptional activity of the latent HIV-1 without inducing the polyclonal activation of non-infected cells. In this sense natural or semisynthetic protein kinase C agonists lacking tumour-promoter activities clearly fulfil this criterion, thereby opening new research avenues to purge HIV-1 reservoirs. In this review article, we have succinctly summarized the known effects of "natural products", focusing on phorboids like prostratin and ingenols, macrolides like bryostatin 1, and macrocyclic polyesters like ingols and jatrophanes. A comprehensive view on the molecular mechanisms underlying the principle of HIV-1 reactivation from latency is provided, discussing the combination of "natural products" with other experimental or conventional therapeutics.
潜伏的 HIV 感染细胞储库的持续存在是接受高效抗逆转录病毒治疗的患者中病毒根除的主要障碍。在不同的 HIV-1 潜伏模型中，部分鉴定了整合的 HIV-1 在潜伏期间被抑制的分子机制，并且已经证明涉及多个过程。因此，已经出现了几种可通过药物处理的分子靶标，以拮抗病毒库中的 HIV-1 潜伏。在这种情况下，有人提出，成功耗尽这些潜伏储库将需要组合使用治疗剂，这些治疗剂可以特异性和有效地作用于携带潜伏 HIV-1 前病毒的细胞。HIV-1 再激活治疗是清除病毒库的潜在治疗选择。该疗法的目标是增强潜伏 HIV-1 的转录活性，而不诱导未感染细胞的多克隆激活。从这个意义上说，缺乏肿瘤促进活性的天然或半合成蛋白激酶 C 激动剂显然符合这一标准，从而为清除 HIV-1 储库开辟了新的研究途径。在这篇综述文章中，我们简明扼要地总结了“天然产物”的已知作用，重点介绍了原番茄素和姜黄素等 phorboids、博莱霉素 1 等大环内酯类、以及 ingols 和 jatrophanes 等大环聚酯类。提供了从潜伏状态激活 HIV-1 的分子机制的全面视图，讨论了“天然产物”与其他实验或常规疗法的组合。
