Alternative promoters drive human cytomegalovirus reactivation from latency

Donna Collins-McMillen, Mike Rak, Jason C. Buehler, Suzu Igarashi-Hayes, Jeremy P. Kamil, Nathaniel J. Moorman, Felicia Goodrum

Research output: Contribution to journalArticle

Abstract

Reactivation from latency requires reinitiation of viral gene expression and culminates in the production of infectious progeny. The major immediate early promoter (MIEP) of human cytomegalovirus (HCMV) drives the expression of crucial lytic cycle transactivators but is silenced during latency in hematopoietic progenitor cells (HPCs). Because the MIEP has poor activity in HPCs, it is unclear how viral transactivators are expressed during reactivation. It has been presumed that viral gene expression is reinitiated via de-repression of the MIEP. We demonstrate that immediate early transcripts arising from reactivation originate predominantly from alternative promoters within the canonical major immediate early locus. Disruption of these intronic promoters results in striking defects in re-expression of viral genes and viral genome replication in the THP-1 latency model. Furthermore, we show that these promoters are necessary for efficient reactivation in primary CD34+ HPCs. Our findings shift the paradigm for HCMV reactivation by demonstrating that promoter switching governs reactivation from viral latency in a context-specific manner.

Original languageEnglish (US)
Pages (from-to)17492-17497
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number35
DOIs
StatePublished - Aug 27 2019

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Viral Genes
Hematopoietic Stem Cells
Cytomegalovirus
Trans-Activators
Virus Latency
Gene Expression
Viral Genome

Keywords

  • Human cytomegalovirus
  • Latency
  • Reactivation

ASJC Scopus subject areas

  • General

Cite this

Alternative promoters drive human cytomegalovirus reactivation from latency. / Collins-McMillen, Donna; Rak, Mike; Buehler, Jason C.; Igarashi-Hayes, Suzu; Kamil, Jeremy P.; Moorman, Nathaniel J.; Goodrum, Felicia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 35, 27.08.2019, p. 17492-17497.

Research output: Contribution to journalArticle

Collins-McMillen, Donna ; Rak, Mike ; Buehler, Jason C. ; Igarashi-Hayes, Suzu ; Kamil, Jeremy P. ; Moorman, Nathaniel J. ; Goodrum, Felicia. / Alternative promoters drive human cytomegalovirus reactivation from latency. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 35. pp. 17492-17497.
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