Rauwel Benjamin, Jang Suk Min, Cassano Marco, Kapopoulou Adamandia, Barde Isabelle, Trono Didier
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Elife. 2015 Apr 7;4:e06068. doi: 10.7554/eLife.06068.
Human cytomegalovirus (HCMV) is a highly prevalent pathogen that induces life-long infections notably through the establishment of latency in hematopoietic stem cells (HSC). Bouts of reactivation are normally controlled by the immune system, but can be fatal in immuno-compromised individuals such as organ transplant recipients. Here, we reveal that HCMV latency in human CD34(+) HSC reflects the recruitment on the viral genome of KAP1, a master co-repressor, together with HP1 and the SETDB1 histone methyltransferase, which results in transcriptional silencing. During lytic infection, KAP1 is still associated with the viral genome, but its heterochromatin-inducing activity is suppressed by mTOR-mediated phosphorylation. Correspondingly, HCMV can be forced out of latency by KAP1 knockdown or pharmacological induction of KAP1 phosphorylation, and this process can be potentiated by activating NFkB with TNF-α. These results suggest new approaches both to curtail CMV infection and to purge the virus from organ transplants.
人巨细胞病毒（HCMV）是一种高度流行的病原体，主要通过在造血干细胞（HSC）中建立潜伏感染而引发终身感染。病毒再激活通常受免疫系统控制，但在免疫功能低下的个体（如器官移植受者）中可能是致命的。在此，我们发现HCMV在人CD34(+) HSC中的潜伏反映了主共抑制因子KAP1、HP1和SETDB1组蛋白甲基转移酶在病毒基因组上的募集，这导致转录沉默。在裂解感染期间，KAP1仍与病毒基因组相关，但mTOR介导的磷酸化抑制了其异染色质诱导活性。相应地，通过敲低KAP1或药理学诱导KAP1磷酸化可使HCMV脱离潜伏状态，并且用TNF-α激活NFkB可增强这一过程。这些结果提示了减少CMV感染以及从器官移植中清除病毒的新方法。
