Latent human herpesvirus 6 is reactivated in CAR T cells

Item Type:	Article
Title:	Latent human herpesvirus 6 is reactivated in CAR T cells
Creators Name:	Lareau, C.A. and Yin, Y. and Maurer, K. and Sandor, K.D. and Daniel, B. and Yagnik, G. and Peña, J. and Crawford, J.C. and Spanjaart, A.M. and Gutierrez, J.C. and Haradhvala, N.J. and Riberdy, J.M. and Abay, T. and Stickels, R.R. and Verboon, J.M. and Liu, V. and Buquicchio, F.A. and Wang, F. and Southard, J. and Song, R. and Li, W. and Shrestha, A. and Parida, L. and Getz, G. and Maus, M.V. and Li, S. and Moore, A. and Roberts, Z.J. and Ludwig, L.S. and Talleur, A.C. and Thomas, P.G. and Dehghani, H. and Pertel, T. and Kundaje, A. and Gottschalk, S. and Roth, T.L. and Kersten, M.J. and Wu, C.J. and Majzner, R.G. and Satpathy, A.T.
Abstract:	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.
Keywords:	Viral DNA, Human Herpesvirus 6, Roseolovirus Infections, T-Lymphocytes, Viral Load
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	623
Page Range:	608-615
Date:	16 November 2023
Official Publication:	https://doi.org/10.1038/s41586-023-06704-2
PubMed:	View item in PubMed

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