HSV activates Akt to trigger calcium release and promote viral entry

Novel candidate target for treatment and suppression

Natalia V. Cheshenko, Janie B. Trepanier, Martha Stefanidou, Niall Buckley, Pablo Gonzalez, William Jacobs, Betsy Herold

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

HSV triggers intracellular calcium release to promote viral entry. We hypothesized that Akt signaling induces the calcium responses and contributes to HSV entry. Exposure of human cervical and primary genital tract epithelial, neuronal, or keratinocyte cells to HSV serotype 2 resulted in rapid phosphorylation of Akt. Silencing of Akt with small interfering RNA prevented the calcium responses, blocked viral entry, and inhibited plaque formation by 90% compared to control siRNA. Susceptibility to infection was partially restored if Akt was reintroduced into silenced cells with an Akt-expressing plasmid. HSV-2 variants deleted in glycoproteins B or D failed to induce Akt phosphorylation, and coimmunoprecipitation studies indicated that Akt interacts with glycoprotein B. Cell-surface expression of Akt was rapidly induced in response to HSV exposure. Miltefosine (50 μM), a licensed drug that blocks Akt phosphorylation, inhibited HSV-induced calcium release, viral entry, and plaque formation following infection with acyclovir-sensitive and resistant clinical isolates. Miltefosine blocked amplification of HSV from explanted ganglia to epithelial cells; viral yields were significantly less in miltefosine compared to control-treated cocultures (P<0.01). Together, these findings identify a novel role for Akt in viral entry, link Akt and calcium signaling, and suggest a new target for HSV treatment and suppression.

Original languageEnglish (US)
Pages (from-to)2584-2599
Number of pages16
JournalFASEB Journal
Volume27
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

miltefosine
Human Herpesvirus 2
Calcium Signaling
Phosphorylation
Calcium
Small Interfering RNA
Glycoproteins
Acyclovir
Coculture Techniques
Infection
Keratinocytes
Ganglia
Plasmids
B-Lymphocytes
Epithelial Cells
Amplification
Pharmaceutical Preparations

Keywords

  • Genital herpes
  • Glycoprotein B
  • Glycoprotein D
  • Miltefosine

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

HSV activates Akt to trigger calcium release and promote viral entry : Novel candidate target for treatment and suppression. / Cheshenko, Natalia V.; Trepanier, Janie B.; Stefanidou, Martha; Buckley, Niall; Gonzalez, Pablo; Jacobs, William; Herold, Betsy.

In: FASEB Journal, Vol. 27, No. 7, 07.2013, p. 2584-2599.

Research output: Contribution to journalArticle

Cheshenko, Natalia V. ; Trepanier, Janie B. ; Stefanidou, Martha ; Buckley, Niall ; Gonzalez, Pablo ; Jacobs, William ; Herold, Betsy. / HSV activates Akt to trigger calcium release and promote viral entry : Novel candidate target for treatment and suppression. In: FASEB Journal. 2013 ; Vol. 27, No. 7. pp. 2584-2599.
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