BackgroundPersistence of latent, replication-competent provirus is the main impediment towards the cure of HIV infection. One of the critical questions concerning HIV latency is the role of integration site selection in HIV expression. Inhibition of the interaction between HIV integrase and its chromatin tethering cofactor LEDGF/p75 is known to reduce integration and to retarget residual provirus to regions resistant to reactivation. LEDGINs, small molecule inhibitors of the interaction between HIV integrase and LEDGF/p75, provide an interesting tool to study the underlying mechanisms. During early infection, LEDGINs block the interaction with LEDGF/p75 and allosterically inhibit the catalytic activity of IN (i.e. the early effect). When present during virus production, LEDGINs interfere with proper maturation due to enhanced IN oligomerization in the progeny virions (i.e. the late effect).ResultsWe studied the effect of LEDGINs present during virus production on the transcriptional state of the residual virus. Infection of cells with viruses produced in the presence of LEDGINs resulted in a residual reservoir that was refractory to activation. Integration of residual provirus was less favored near epigenetic markers associated with active transcription. However, integration near H3K36me3 and active genes, both targeted by LEDGF/p75, was not affected. Also in primary cells, LEDGIN treatment induced a reservoir resistant to activation due to a combined early and late effect.ConclusionLEDGINs present a research tool to study the link between integration and transcription, an essential question in retrovirology. LEDGIN treatment during virus production altered integration of residual provirus in a LEDGF/p75-independent manner, resulting in a reservoir that is refractory to activation.

中文翻译：

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病毒生产过程中 LEDGIN 处理对残留 HIV-1 转录的影响

背景潜伏的、有复制能力的原病毒的持续存在是治愈 HIV 感染的主要障碍。关于 HIV 潜伏期的关键问题之一是整合位点选择在 HIV 表达中的作用。已知抑制 HIV 整合酶与其染色质束缚辅因子 LEDGF/p75 之间的相互作用会减少整合并将残留的原病毒重新定位到抗再激活的区域。LEDGIN 是 HIV 整合酶和 LEDGF/p75 之间相互作用的小分子抑制剂，为研究潜在机制提供了一种有趣的工具。在早期感染期间，LEDGIN 阻断与 LEDGF/p75 的相互作用并变构抑制 IN 的催化活性（即早期效应）。在病毒生产过程中出现时，由于子代病毒粒子中增强的 IN 寡聚化（即后期效应），LEDGIN 会干扰适当的成熟。结果我们研究了病毒生产过程中存在的 LEDGIN 对残留病毒转录状态的影响。在 LEDGIN 存在下产生的病毒感染细胞导致残留的储库难以激活。残留原病毒的整合在与活性转录相关的表观遗传标记附近不太受欢迎。然而，LEDGF/p75 靶向的 H3K36me3 和活性基因附近的整合不受影响。同样在原代细胞中，由于早期和晚期效应的结合，LEDGIN 处理诱导了一个抗激活的储库。结论 LEDGIN 提供了一种研究工具来研究整合和转录之间的联系，这是逆转录病毒学中的一个基本问题。