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Latent human herpesvirus 6 is reactivated in chimeric antigen receptor T cells

ABSTRACT: Cell therapies have yielded durable clinical benefits for patients with cancer but have been accompanied by unexpected side effects of treatment, including neurotoxicity. Currently, we lack a comprehensive understanding of the mechanisms of toxicity observed in patients receiving cell therapies, including encephalitis caused by human herpesvirus 6 (HHV-6) that has been repeatedly reported. Here, via comprehensive viral RNA data mining, we examine the landscape of human latent viral reactivation, revealing that HHV-6B can become reactivated in human CD4+ T cells in standard in vitro cultures. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (~1 in 360-10,000 cells) that possess high viral transcriptional activity in chimeric antigen receptor (CAR) T cell culture before spreading rapidly to infect other cells in vitro. Through the reanalysis of single-cell sequencing data from FDA-approved cell therapy products, we identify the presence of CAR+, HHV-6 super-expressor T cells in human patients in vivo. Together, our study implicates cell therapy products as the source of lytic HHV-6 repeatedly reported in clinical trialsand has broad implications for the design, screening, and interpretation of unexpected toxicities in cell therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210063 | GEO | 2023/08/05

REPOSITORIES: GEO

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