细胞疗法为癌症患者带来了持久的临床益处，但与开发受操纵的人类细胞疗法相关的风险尚未得到充分研究。例如，我们对接受 T 细胞疗法的患者中观察到的毒性机制缺乏全面的了解，包括最近关于人类疱疹病毒 6 (HHV-6)1 重新激活引起脑炎的报道。在这里，通过拍碱基规模的病毒基因组学挖掘，我们检查了人类潜伏病毒重新激活的情况，并证明 HHV-6B 可以在人类 CD4 T 细胞培养物中重新激活。通过单细胞测序，我们在研究级同种异体嵌合抗原受体 (CAR) T 细胞中鉴定出了具有高病毒转录活性的罕见 HHV-6“超级表达细胞”群体（约 300-10,000 个细胞中就有 1 个）。通过分析接受美国食品和药物管理局批准的细胞治疗产品2或正在进行临床研究3-5的患者的单细胞测序数据，我们确定了患者体内是否存在 HHV-6 超表达 CAR T 细胞。总之，我们的研究结果证明了综合基因组学分析的效用，表明细胞治疗产品是造成溶解性 HHV-6 感染的潜在来源，这种感染已在临床试验中报告1,6-8，并可能影响细胞治疗产品的设计和生产。自体和同种异体细胞疗法。© 2023。作者，获得 Springer Nature Limited 的独家许可。

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.