Latent human herpesvirus 6 is reactivated in CAR T cells

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Item Type:	Article
Title:	Latent human herpesvirus 6 is reactivated in CAR T cells
Creators Name:	Lareau, C.A., Yin, Y., Maurer, K., Sandor, K.D., Daniel, B., Yagnik, G., Peña, J., Crawford, J.C., Spanjaart, A.M., Gutierrez, J.C., Haradhvala, N.J., Riberdy, J.M., Abay, T., Stickels, R.R., Verboon, J.M., Liu, V., Buquicchio, F.A., Wang, F., Southard, J., Song, R., Li, W., Shrestha, A., Parida, L., Getz, G., Maus, M.V., Li, S., Moore, A., Roberts, Z.J., Ludwig, L.S., Talleur, A.C., Thomas, P.G., Dehghani, H., Pertel, T., Kundaje, A., Gottschalk, S., Roth, T.L., Kersten, M.J., Wu, C.J., 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
Additional Information:	Copyright © The Author(s), under exclusive licence to Springer Nature Limited 2023
Official Publication:	https://doi.org/10.1038/s41586-023-06704-2
External Fulltext:	View full text on external repository or document server
PubMed:	View item in PubMed

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