Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06519, USA.
Viruses. 2021 Sep 17;13(9):1858. doi: 10.3390/v13091858.
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.
超过 50%的 HIV-1 潜伏库是通过克隆扩张维持的。克隆扩张的 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。在长期接受抑制性抗逆转录病毒治疗 (ART) 的个体中，HIV-1 整合位点在特定癌症相关基因的特定位置富集，与宿主转录单元的方向相同。单细胞转录组分析显示，HIV-1 通过 HIV-1 到宿主 RNA 剪接导致异常的癌症相关基因表达。此外，HIV-1 启动子优于宿主基因启动子，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中并导致致癌基因获得功能或肿瘤抑制基因失活时，HIV-1 插入诱变会驱动 HIV-1 感染细胞的增殖，并在极少数情况下可能导致癌症。HIV-1 在整合位点驱动的异常癌症相关基因表达可通过 CRISPR 介导的 HIV-1 启动子抑制或 HIV-1 抑制剂来抑制。鉴于 ART 不能抑制 HIV-1 启动子活性，因此应探索抑制 HIV-1 转录和阻止 HIV-1 感染细胞克隆扩张的治疗剂，以阻断 HIV-1 潜伏库的克隆扩张。
