More than 50% of the HIV-1 latent reservoir is maintained by clonal expansion. The clonally expanded HIV-1-infected cells can contribute to persistent nonsuppressible low-level viremia and viral rebound. HIV-1 integration site and proviral genome landscape profiling reveals the clonal expansion dynamics of HIV-1-infected cells. In individuals under long-term suppressive antiretroviral therapy (ART), HIV-1 integration sites are enriched in specific locations in certain cancer-related genes in the same orientation as the host transcription unit. Single-cell transcriptome analysis revealed that HIV-1 drives aberrant cancer-related gene expression through HIV-1-to-host RNA splicing. Furthermore, the HIV-1 promoter dominates over the host gene promoter and drives high levels of cancer-related gene expression. When HIV-1 integrates into cancer-related genes and causes gain of function of oncogenes or loss of function of tumor suppressor genes, HIV-1 insertional mutagenesis drives the proliferation of HIV-1-infected cells and may cause cancer in rare cases. HIV-1-driven aberrant cancer-related gene expression at the integration site can be suppressed by CRISPR-mediated inhibition of the HIV-1 promoter or by HIV-1 suppressing agents. Given that ART does not suppress HIV-1 promoter activity, therapeutic agents that suppress HIV-1 transcription and halt the clonal expansion of HIV-1-infected cells should be explored to block the clonal expansion of the HIV-1 latent reservoir.

中文翻译：

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HIV-1 储库的克隆扩增动力学：整合位点依赖性增殖和 HIV-1 持久性的机制


超过 50% 的 HIV-1 潜伏病毒库是通过克隆扩增来维持的。克隆扩增的 HIV-1 感染细胞可导致持续的不可抑制的低水平病毒血症和病毒反弹。 HIV-1 整合位点和前病毒基因组景观分析揭示了 HIV-1 感染细胞的克隆扩张动态。在接受长期抑制性抗逆转录病毒治疗（ART）的个体中，HIV-1整合位点在某些癌症相关基因的特定位置富集，其方向与宿主转录单位相同。单细胞转录组分析表明，HIV-1 通过 HIV-1 与宿主 RNA 剪接驱动癌症相关基因的异常表达。此外，HIV-1启动子主导宿主基因启动子并驱动高水平的癌症相关基因表达。当 HIV-1 整合到癌症相关基因并导致癌基因功能获得或抑癌基因功能丧失时，HIV-1 插入突变会驱动 HIV-1 感染细胞增殖，在极少数情况下可能导致癌症。 HIV-1 驱动的整合位点异常癌症相关基因表达可以通过 CRISPR 介导的 HIV-1 启动子抑制或 HIV-1 抑制剂来抑制。鉴于 ART 不会抑制 HIV-1 启动子活性，因此应探索抑制 HIV-1 转录并阻止 HIV-1 感染细胞克隆扩增的治疗药物，以阻止 HIV-1 潜伏库的克隆扩增。