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.
Funder
HHS | National Institutes of Health
American Heart Association
American Cancer Society
Publisher
Proceedings of the National Academy of Sciences
Reference55 articles.
1. Overview of human cytomegalovirus pathogenesis;Nogalski,2014
2. Cytomegaloviruses;Mocarski,2013
3. M. F. Stinski , J. L. Meier , “Immediate-early viral gene regulation and function” in Human Herpesviruses, T. Biology ., Eds. (Cambridge University Press, Cambridge, UK, 2007), chap. 17.
4. Human cytomegalovirus latency: Approaching the Gordian knot;Goodrum;Annu. Rev. Virol.,2016
5. Molecular determinants and the regulation of human cytomegalovirus latency and reactivation;Collins-McMillen;Viruses,2018
Cited by
53 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献