Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells.
Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells.
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DOI：
10.1371/journal.pone.0074163
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cihlar T
中科院分区：
文献类型：
--
作者：
Balakrishnan M;Yant SR;Tsai L;O'Sullivan C;Bam RA;Tsai A;Niedziela-Majka A;Stray KM;Sakowicz R;Cihlar T
HIV-1整合酶（IN）是两类抗逆转录病毒药物的靶点：i）整合酶链转移抑制剂（INSTI）和ii）非催化位点整合酶抑制剂（NCINI）。NCINI结合在IN二聚体界面处，并且被认为主要通过阻断IN-vDNA组装以及IN-LEDGF/p75相互作用来干扰靶细胞中的病毒DNA（vDNA）整合。在此，我们表明，处理病毒产生细胞，而不是成熟的病毒粒子或靶细胞，驱动NCINI抗病毒效力。NCINIs靶向HIV复制中的一个基本晚期事件，该事件对生产细胞中的LEDGF水平不敏感。在NCINI存在下产生的病毒颗粒显示正常的Gag-Pol加工和内源性逆转录酶活性，但在进入靶细胞后启动vDNA合成时有缺陷。在IN二聚体界面中携带T174 I突变的NCINI耐药病毒对化合物诱导的晚期效应（包括逆转录阻断）不太敏感。野生型，但不是T174 I病毒，在NCINI的存在下产生的核心形态中表现出显着的缺陷和IN寡聚体的水平增加，这在成熟的无细胞颗粒处理后没有观察到。总的来说，这些结果表明，NCINI通过一种新的机制，这是无关的，以前观察到的抑制IN活性或IN-LEDGF相互作用，而是涉及在HIV-1核心成熟和组装过程中的IN功能的破坏。
HIV-1 integrase (IN) is the target for two classes of antiretrovirals: i) the integrase strand-transfer inhibitors (INSTIs) and ii) the non-catalytic site integrase inhibitors (NCINIs). NCINIs bind at the IN dimer interface and are thought to interfere primarily with viral DNA (vDNA) integration in the target cell by blocking IN-vDNA assembly as well as the IN-LEDGF/p75 interaction. Herein we show that treatment of virus-producing cells, but not of mature virions or target cells, drives NCINI antiviral potency. NCINIs target an essential late-stage event in HIV replication that is insensitive to LEDGF levels in the producer cells. Virus particles produced in the presence of NCINIs displayed normal Gag-Pol processing and endogenous reverse transcriptase activity, but were defective at initiating vDNA synthesis following entry into the target cell. NCINI-resistant virus carrying a T174I mutation in the IN dimer interface was less sensitive to the compound-induced late-stage effects, including the reverse transcription block. Wild-type, but not T174I virus, produced in the presence of NCINIs exhibited striking defects in core morphology and an increased level of IN oligomers that was not observed upon treatment of mature cell-free particles. Collectively, these results reveal that NCINIs act through a novel mechanism that is unrelated to the previously observed inhibition of IN activity or IN-LEDGF interaction, and instead involves the disruption of an IN function during HIV-1 core maturation and assembly.
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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通讯作者：
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