FOXO transcription factors activate alternative major immediate early promoters to induce human cytomegalovirus reactivation.

Proceedings of the National Academy of Sciences of the United States of America
Andrew E HaleNathaniel J Moorman

Abstract

Human progenitor cells (HPCs) support human cytomegalovirus (HCMV) latency, and their differentiation along the myeloid lineage triggers cellular cues that drive reactivation. A key step during HCMV reactivation in latently infected HPCs is reexpression of viral major immediate early (MIE) genes. We recently determined that the major immediate early promoter (MIEP), which is primarily responsible for MIE gene expression during lytic replication, remains silent during reactivation. Instead, alternative promoters in the MIE locus are induced by reactivation stimuli. Here, we find that forkhead family (FOXO) transcription factors are critical for activation of alternative MIE promoters during HCMV reactivation, as mutating FOXO binding sites in alternative MIE promoters decreased HCMV IE gene expression upon reactivation and significantly decreased the production of infectious virus from latently infected primary CD34+ HPCs. These findings establish a mechanistic link by which infected cells sense environmental cues to regulate latency and reactivation, and emphasize the role of contextual activation of alternative MIE promoters as the primary drivers of reactivation.

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Citations

Oct 20, 2020·Frontiers in Cellular and Infection Microbiology·Donna Collins-McMillenFelicia Goodrum
Oct 30, 2020·Pathogens·Abigail L Dooley, Christine M O'Connor
Jul 25, 2021·International Journal of Molecular Sciences·Daniel G SausenRonen Borenstein
Jun 16, 2021·Annual Review of Virology·Andrew E Hale, Nathaniel J Moorman

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