Margolis David M, Archin Nancy M
Departments of Medicine, Microbiology and Immunology, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7435, USA.
Infect Disord Drug Targets. 2006 Dec;6(4):369-76. doi: 10.2174/187152606779025824.
The therapeutic armamentarium for human immunodeficiency virus type 1 (HIV-1) infection continues to expand. New targets such as entry and integration have recently been successfully exploited. However, HIV-infected patients in need of treatment are currently committed to lifelong suppressive therapy. The persistence of integrated HIV DNA genomes capable of producing virus is a fundamental obstacle to the eradication or cure of HIV infection. Rational molecular or pharmacologic strategies to eliminate persistent HIV proviral genomes are an unaddressed therapeutic need. Coupled with potent antiretroviral therapy, treatments that could efficiently deplete the persistent DNA reservoir of HIV could radically alter treatment paradigms. Prior attempts to target persistent proviral infection deployed intensive antiretroviral therapy (ART) in combination with global inducers of T-cell activation. Initial trials of this approach were unsuccessful. Non-specific T-cell activation may induce high-level viral replication above a level that can be fully contained by ART, while increasing the susceptibility of uninfected cells. Selective targeting of HIV provirus via agents that induce the expression of quiescent HIV, but have limited effects on the uninfected host cell is an alternate approach to attack latent HIV. Recent studies define the role of repressive chromatin structure in maintaining HIV quiescence, and suggest that mechanisms that remodel chromatin about the HIV promoter are a possible therapeutic target. Other studies have uncovered specific factors that may act to induce or maintain latency by limiting the efficiency of HIV gene expression. Attempts to deplete latent HIV using drugs that alter chromatin structure have entered clinical study.
用于治疗1型人类免疫缺陷病毒（HIV-1）感染的治疗手段不断增加。诸如病毒进入和整合等新靶点最近已被成功利用。然而，目前需要治疗的HIV感染患者仍需终身接受抑制性治疗。能够产生病毒的整合型HIV DNA基因组的持续存在是根除或治愈HIV感染的一个基本障碍。消除持续性HIV前病毒基因组的合理分子或药理学策略是一个尚未得到解决的治疗需求。与强效抗逆转录病毒疗法相结合，能够有效清除HIV持续性DNA储存库的治疗方法可能会从根本上改变治疗模式。此前针对持续性前病毒感染的尝试采用了强化抗逆转录病毒疗法（ART）并结合T细胞激活的全身性诱导剂。这种方法的初步试验并不成功。非特异性T细胞激活可能会诱导高水平的病毒复制，其水平超过ART所能完全控制的范围，同时增加未感染细胞的易感性。通过诱导静止HIV表达但对未感染宿主细胞影响有限的药物选择性靶向HIV前病毒是攻击潜伏HIV的另一种方法。最近的研究确定了抑制性染色质结构在维持HIV静止状态中的作用，并表明重塑HIV启动子周围染色质的机制是一个可能的治疗靶点。其他研究发现了一些特定因素，这些因素可能通过限制HIV基因表达的效率来诱导或维持潜伏状态。使用改变染色质结构的药物来清除潜伏HIV的尝试已进入临床研究阶段。
