Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), 69120 Heidelberg, Germany.
Health Data Science Unit, Medical Faculty University Heidelberg and BioQuant, 69120 Heidelberg, Germany.
Cell Rep. 2023 Feb 28;42(2):112110. doi: 10.1016/j.celrep.2023.112110. Epub 2023 Feb 13.
HIV-1 encounters the hierarchically organized host chromatin to stably integrate and persist in anatomically distinct latent reservoirs. The contribution of genome organization in HIV-1 infection has been largely understudied across different HIV-1 targets. Here, we determine HIV-1 integration sites (ISs), associate them with chromatin and expression signatures at different genomic scales in a microglia cell model, and profile them together with the primary T cell reservoir. HIV-1 insertions into introns of actively transcribed genes with IS hotspots in genic and super-enhancers, characteristic of blood cells, are maintained in the microglia cell model. Genome organization analysis reveals dynamic CCCTC-binding factor (CTCF) clusters in cells with active and repressed HIV-1 transcription, whereas CTCF removal impairs viral integration. We identify CTCF-enriched topologically associated domain (TAD) boundaries with signatures of transcriptionally active chromatin as HIV-1 integration determinants in microglia and CD4 T cells, highlighting the importance of host genome organization in HIV-1 infection.
HIV-1 遇到组织层次分明的宿主染色质，从而稳定地整合并存在于解剖学上不同的潜伏库中。在不同的 HIV-1 靶标中，基因组组织在 HIV-1 感染中的作用在很大程度上还没有得到充分研究。在这里，我们确定了 HIV-1 整合位点（IS），并将其与染色质和不同基因组尺度的表达特征相关联，在小神经胶质细胞模型中进行了分析，并与主要 T 细胞库一起进行了分析。HIV-1 插入到基因的内含子中，在基因和超级增强子中具有 IS 热点，这是血细胞的特征，在小神经胶质细胞模型中得以维持。基因组组织分析显示，在具有活跃和抑制 HIV-1 转录的细胞中，CCCTC 结合因子（CTCF）簇是动态的，而 CTCF 的去除则会损害病毒的整合。我们确定了富含 CTCF 的拓扑关联域（TAD）边界，这些边界具有转录活跃染色质的特征，是小神经胶质细胞和 CD4 T 细胞中 HIV-1 整合的决定因素，突出了宿主基因组组织在 HIV-1 感染中的重要性。
