Latent human herpesvirus 6 is reactivated in CAR T cells


  • C.A. Lareau
  • Y. Yin
  • K. Maurer
  • K.D. Sandor
  • B. Daniel
  • G. Yagnik
  • J. Peña
  • J.C. Crawford
  • A.M. Spanjaart
  • J.C. Gutierrez
  • N.J. Haradhvala
  • J.M. Riberdy
  • T. Abay
  • R.R. Stickels
  • J.M. Verboon
  • V. Liu
  • F.A. Buquicchio
  • F. Wang
  • J. Southard
  • R. Song
  • W. Li
  • A. Shrestha
  • L. Parida
  • G. Getz
  • M.V. Maus
  • S. Li
  • A. Moore
  • Z.J. Roberts
  • L.S. Ludwig
  • A.C. Talleur
  • P.G. Thomas
  • H. Dehghani
  • T. Pertel
  • A. Kundaje
  • S. Gottschalk
  • T.L. Roth
  • M.J. Kersten
  • C.J. Wu
  • R.G. Majzner
  • A.T. Satpathy


  • Nature


  • Nature 623: 608-615


  • 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). 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 Administration or are in clinical studies, 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 trials and may influence the design and production of autologous and allogeneic cell therapies.