Human cytomegalovirus requires epidermal growth factor receptor signaling to enter and initiate the early steps in the establishment of latency in CD34+ human progenitor cells

Jung Heon Kim, Donna Collins-McMillen, Jason C. Buehler, Felicia Goodrum, Andrew D. Yurochko

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The establishment of human cytomegalovirus (HCMV) latency and persistence relies on the successful infection of hematopoietic cells, which serve as sites of viral persistence and contribute to viral spread. Here, using blocking antibodies and pharmacological inhibitors, we document that HCMV activation of the epidermal growth factor receptor (EGFR) and downstream phosphatidylinositol 3-kinase (PI3K) mediates viral entry into CD34+ human progenitor cells (HPCs), resulting in distinct cellular trafficking and nuclear translocation of the virus compared to that in other immune cells, such as we have documented in monocytes. We argue that the EGFR allows HCMV to regulate the cellular functions of these replication-restricted cells via its signaling activity following viral binding. In addition to regulating HCMV entry/trafficking, EGFR signaling may also shape the early steps required for the successful establishment of viral latency in CD34+ cells, as pharmacological inhibition of EGFR increases the transcription of lytic IE1/IE2 mRNA while curbing the expression of latency-associated UL138 mRNA. EGFR signaling following infection of CD34+ HPCs may also contribute to changes in hematopoietic potential, as treatment with the EGFR kinase (EGFRK) inhibitor AG1478 alters the expression of the cellular hematopoietic cytokine interleukin 12 (IL-12) in HCMV-infected cells but not in mockinfected cells. These findings, along with our previous work with monocytes, suggest that EGFR likely serves as an important determinant of HCMV tropism for select subsets of hematopoietic cells. Moreover, our new data suggest that EGFR is a key receptor for efficient viral entry and that the ensuing signaling regulates important early events required for successful infection of CD34+ HPCs by HCMV.

Original languageEnglish (US)
Article numbere01206-16
JournalJournal of Virology
Volume91
Issue number5
DOIs
StatePublished - 2017

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Human herpesvirus 5
Cytomegalovirus
Epidermal Growth Factor Receptor
stem cells
Stem Cells
cells
monocytes
infection
Monocytes
tropisms
Infection
epidermal growth factor receptors
Phosphatidylinositol 3-Kinase
Pharmacology
interleukin-12
Virus Latency
phosphatidylinositol 3-kinase
Messenger RNA
Tropism
Blocking Antibodies

Keywords

  • CD34 HPC
  • EGFR
  • HCMV
  • Latency
  • Virus entry

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Human cytomegalovirus requires epidermal growth factor receptor signaling to enter and initiate the early steps in the establishment of latency in CD34+ human progenitor cells. / Kim, Jung Heon; Collins-McMillen, Donna; Buehler, Jason C.; Goodrum, Felicia; Yurochko, Andrew D.

In: Journal of Virology, Vol. 91, No. 5, e01206-16, 2017.

Research output: Contribution to journalArticle

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