Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom.
mBio. 2021 Jun 29;12(3):e0022721. doi: 10.1128/mBio.00227-21. Epub 2021 Jun 1.
Human cytomegalovirus (HCMV) presents a major health burden in the immunocompromised and in stem cell transplant medicine. A lack of understanding about the mechanisms of HCMV latency in undifferentiated CD34 stem cells, and how latency is broken for the virus to enter the lytic phase of its infective cycle, has hampered the development of essential therapeutics. Using a human induced pluripotent stem cell (iPSC) model of HCMV latency and patient-derived myeloid cell progenitors, we demonstrate that bone morphogenetic protein receptor type 2 (BMPR2) is necessary for HCMV latency. In addition, we define a crucial role for the transcription factor Yin Yang 1 (YY1) in HCMV latency; high levels of YY1 are maintained in latently infected cells as a result of BMPR2 signaling through the SMAD4/SMAD6 axis. Activation of SMAD4/6, through BMPR2, inhibits TGFbeta receptor signaling, which leads to the degradation of YY1 via induction of a cellular microRNA (miRNA), hsa-miR-29a. Pharmacological targeting of BMPR2 in progenitor cells results in the degradation of YY1 and an inability to maintain latency and renders cells susceptible to T cell killing. These data argue that BMPR2 plays a role in HCMV latency and is a new potential therapeutic target for maintaining or disrupting HCMV latency in myeloid progenitors. Understanding the mechanisms which regulate HCMV latency could allow therapeutic targeting of the latent virus reservoir from where virus reactivation can cause severe disease. We show that the BMPR2/TGFbeta receptor/YY1 signaling axis is crucial to maintain HCMV latency in undifferentiated cells and that pharmacological reduction of BMPR2 in latently infected cells leads to reactivation of the viral lytic transcription program, which renders the infected cell open to immune detection and clearance in infected individuals. Therefore, this work identifies key host-virus interactions which regulate HCMV latent infection. It also demonstrates a potential new therapeutic approach to reduce HCMV reactivation-mediated disease by the treatment of donor stem cells/organs prior to transplantation, which could have a major impact in the transplant disease setting.
人巨细胞病毒（HCMV）在免疫功能低下和干细胞移植医学中带来了重大的健康负担。由于缺乏对未分化 CD34 干细胞中 HCMV 潜伏机制的了解，以及对病毒如何进入其感染周期裂解相的了解，阻碍了必要治疗方法的发展。我们使用人诱导多能干细胞（iPSC）HCMV 潜伏模型和患者来源的髓系细胞前体，证明骨形态发生蛋白受体 2（BMPR2）是 HCMV 潜伏所必需的。此外，我们确定转录因子 Yin Yang 1（YY1）在 HCMV 潜伏中的关键作用；由于 BMPR2 通过 SMAD4/SMAD6 轴信号传导，高水平的 YY1 保持在潜伏感染的细胞中。通过 BMPR2 激活 SMAD4/6，抑制 TGFbeta 受体信号，导致 YY1 通过诱导细胞 microRNA（miRNA）hsa-miR-29a 降解。在祖细胞中靶向 BMPR2 的药物治疗导致 YY1 降解，无法维持潜伏并使细胞易受 T 细胞杀伤。这些数据表明 BMPR2 在 HCMV 潜伏中起作用，是维持或破坏髓系祖细胞中 HCMV 潜伏的新潜在治疗靶点。了解调节 HCMV 潜伏的机制可以允许针对潜伏病毒库的治疗靶向，其中病毒重新激活可能导致严重疾病。我们表明，BMPR2/TGFbeta 受体/YY1 信号轴对于维持未分化细胞中的 HCMV 潜伏至关重要，并且在潜伏感染细胞中降低 BMPR2 的药物治疗会导致病毒裂解转录程序的重新激活，从而使感染细胞对受感染个体中的免疫检测和清除开放。因此，这项工作确定了调节 HCMV 潜伏感染的关键宿主-病毒相互作用。它还证明了一种潜在的新治疗方法，通过在移植前治疗供体干细胞/器官来减少 HCMV 再激活介导的疾病，这可能会对移植疾病环境产生重大影响。
