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HIV-1 DNA integration: advancing anti-HIV-1 genetherapy approaches by blocking and modulating theprocess

机译：HIV-1 DNA整合：通过阻断和调节过程来推进抗HIV-1基因治疗方法

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The efficient replication of retroviruses requires integration of the double-stranded DNA copy of viral RNA into chromosomal DNA of the infected host cell. Integration for all retroviruses, including human immunodeficiency virus type 1 (HIV-1), represents the stable incorporation of viral DNA into that of the host and depends upon the function of the viral encoded enzyme, integrase (IN). Among various classes of animal viruses, integration of viral DNA is a unique and defining step in the life cycle of retroviruses and results in the permanent establishment of the viral genome in the infected host cell. The practical consequences of this activity is the presence of a viral DNA template capable of directing the production of progeny virus for the life span of the infected cell. This template persists even despite the imposition of therapeutic regimens available currently that involve the combinatorial use of inhibitors against HIV-1 reverse transcriptase (RT) and protease (PR) that are effective in reducing circulating virus in most HIV-1 seropositive patients. Efficient blockade of integration, or the steps preceding integration, would be far preferable than attempts to suppress the production of viral products from cells that already harbor an HIV-1 provirus.The actual mechanistic details for integration of all retroviruses is remarkably similar and such an understanding is vital in a new era of rational drug design that not only relies upon an intimate knowledge of the structure and function of individual viral products, but alternatively utilizes those details to manipulate these products with the goal of halting viral replication completely or ablating the presence of infected host cells in the seropositive patient. Several small molecule inhibitors of HIV-1 integrase are in development with the eventual hope of including such compounds in combination therapy with PR and RT inhibitors. However, there are anti-IN gene therapy strategies being pursued that are highlighted in this review and which can be employed to inhibit function of the protein with a similar goal of blocking HIV-1 infection within host cells.
机译：逆转录病毒的有效复制需要将病毒RNA的双链DNA拷贝整合到感染宿主细胞的染色体DNA中。包括人类免疫缺陷病毒1型（HIV-1）在内的所有逆转录病毒的整合代表了将病毒DNA稳定整合到宿主的体内，并取决于病毒编码酶整合酶（IN）的功能。在各种类型的动物病毒中，病毒DNA的整合是逆转录病毒生命周期中一个独特的决定性步骤，并导致病毒基因组在感染宿主细胞中的永久建立。这项活动的实际后果是存在病毒DNA模板，该模板能够指导受感染细胞寿命内子代病毒的产生。即使强加了目前可用的治疗方案，该模板仍然存在，该治疗方案涉及可有效减少大多数HIV-1血清反应阳性患者循环病毒的HIV-1逆转录酶（RT）和蛋白酶（PR）抑制剂的组合使用。与试图抑制已经携带HIV-1前病毒的细胞产生病毒产物的尝试相比，有效地阻止整合或整合之前的步骤要好得多。所有逆转录病毒整合的实际机制细节非常相似，因此，在新的理性药物设计时代，理解不仅是对单个病毒产品的结构和功能的深入了解，而且还是利用这些细节来操纵这些产品，以彻底停止病毒复制或消除病毒的存在，这一点至关重要。血清反应阳性患者中感染宿主细胞的数量。 HIV-1整合酶的几种小分子抑制剂正在开发中，最终希望将此类化合物与PR和RT抑制剂联合治疗。但是，本综述着重介绍了抗-IN基因治疗策略，该策略可用于抑制蛋白质功能，以阻止宿主细胞内HIV-1感染为类似目标。

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