Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Baldiri i Reixac 4, E-08028 Barcelona, Spain.
J Virol. 2011 Apr;85(7):3187-202. doi: 10.1128/JVI.01920-10. Epub 2011 Jan 26.
The establishment of a stable reservoir of latently infected cells allows HIV to persist in the host. Usually, HIV infection of T cells results in integration of the viral genome, with a preference for regions in the human genome containing active genes, viral expression, and production of new viruses. However, in rare cases T cells become latently infected, and this is presumed to be due to a combination of two factors: integrated viruses are not efficiently transcribed and infected T cells revert to a resting memory state. HIV latency has been associated with provirus integration in regions of constitutive heterochromatin, gene deserts, or very highly expressed genes. We have investigated the transcriptional consequences of latent HIV integration into cellular genes and the involvement of chromatin reassembly factors (CRFs) in the transcriptional interference that a host gene exerts on the integrated cryptic HIV promoter. Chimeric transcripts containing sequences from the host gene and HIV can be detected, having been initiated at promoters of either the cell or the virus. Reactivation of HIV downregulates host gene expression. Cryptic promoters might remain inactive due to the repressive chromatin configuration established by CRFs during transcription elongation. Depletion of CRFs such as Spt6, Chd1, and FACT, or the histone chaperones ASF1a and HIRA, promoted HIV reactivation, concomitantly with chromatin relaxation and a decrease in general RNA polymerase activity. Overall, our results indicate that CRFs play a role in maintaining HIV latency by transcriptional interference when the provirus is integrated into an intron of a highly active gene.
潜伏感染细胞库的建立使 HIV 能够在宿主体内存活。通常，HIV 感染 T 细胞会导致病毒基因组的整合，并且偏好整合到人类基因组中含有活性基因、病毒表达和产生新病毒的区域。然而，在极少数情况下，T 细胞会潜伏感染，这被认为是两个因素的结合：整合的病毒转录效率不高，感染的 T 细胞恢复到静止的记忆状态。HIV 潜伏与前病毒整合到组成型异染色质、基因荒漠或高度表达的基因有关。我们研究了潜伏 HIV 整合到细胞基因中的转录后果，以及染色质重组装因子（CRFs）在宿主基因对整合的隐蔽 HIV 启动子产生的转录干扰中的作用。可以检测到包含宿主基因和 HIV 序列的嵌合转录本，这些转录本是从细胞或病毒的启动子起始的。HIV 的重新激活会下调宿主基因的表达。隐蔽的启动子可能由于 CRFs 在转录延伸过程中建立的抑制性染色质构象而保持不活跃。CRFs 的耗竭，如 Spt6、Chd1 和 FACT，或组蛋白伴侣 ASF1a 和 HIRA，促进了 HIV 的重新激活，同时伴随着染色质松弛和一般 RNA 聚合酶活性的降低。总的来说，我们的结果表明，当前病毒整合到一个高度活跃基因的内含子时，CRFs 通过转录干扰在维持 HIV 潜伏中发挥作用。
