Attacking latent HIV provirus: from mechanism to therapeutic strategies
Attacking latent HIV provirus: from mechanism to therapeutic strategies
复制标题
DOI：
10.1097/01.coh.0000203837.47092.fd
复制
发表时间：
2006-03-01
影响因子：
4.1
通讯作者：
Margolis, David M.
中科院分区：
文献类型：
--
作者：
Archin, Nancy M.;Margolis, David M.
目的综述能够在长寿命的CD4T细胞内表达HIV的小群体整合前HIV基因组的持久性是根除或治愈HIV感染的根本障碍。由于有效的抗逆转录病毒治疗本身似乎是一种不切实际的方法来根除这个静止的艾滋病毒感染宿主，因此需要新的方法。最近的发现初步研究未能证明同时的、强化的抗逆转录病毒治疗与全球CD4T细胞激活的诱导剂相结合可以根除艾滋病毒感染。全球T细胞激活可能会诱导病毒复制，并使易感、未感染的靶细胞数量超过当前抗逆转录病毒疗法所能控制的门槛。然而，未来抗逆转录病毒治疗的进展可能会改变这一平衡。另一种克服HIV潜伏期的方法是开发能够诱导静止的HIV表达而不增加从头感染的药物。更有选择性、更有针对性的方法可能会通过导致平行T细胞激活的信号来避免病毒诱导的不良后果。最近，使用细胞因子IL 7、新型蛋白激酶激动剂前列腺素和染色质重塑酶组蛋白脱乙酰酶抑制剂的方法已进入高级临床前和临床试验。然而，在实用的、有针对性的方法方面取得了令人鼓舞的进展，这些方法是在静息的CD4T细胞内持续存在的主要储存库，但开始进入临床测试。
Purpose of reviewThe persistence of small population integrated proviral HIV genomes capable of expressing HIV within long-lived CD4 T cells is a fundamental obstacle to the eradication or cure of HIV infection. As potent antiretroviral therapy by itself appears to be an impractical approach to the eradication of this quiescent reservoir of HIV infection, new approaches are required.Recent findingsInitial studies failed to demonstrate that simultaneous, intensive antiretroviral therapy in combination with global inducers of CD4 T-cell activation could eradicate HIV infection. Global T-cell activation may induce viral replication and increase the number of susceptible uninfected target cells beyond the threshold that can be contained by current antiretroviral therapy. Future advances in antiretroviral therapy may, however, change this equation. An alternative approach to overcoming HIV latency is to develop agents capable of inducing the expression of quiescent HIV without enhancing de novo infection. More selective, targeted approaches may avoid the undesirable consequences of viral induction via signals that result in parallel T-cell activation. Such approaches using the cytokine IL 7, the novel protein kinase agonist prostratin, and inhibitors of the chromatin remodeling enzyme histone deacetylase have recently entered advanced preclinical and clinical testing.SummaryMany obstacles to the eradication of HIV infection exist. Encouraging advances in practical, targeted approaches to the major reservoir of persistence within resting CD4 T cells are, however, beginning to enter clinical testing.