Aberrant regulation of the Akt signaling network by human cytomegalovirus allows for targeting of infected monocytes

Antiviral Res. 2018 Oct:158:13-24. doi: 10.1016/j.antiviral.2018.07.015. Epub 2018 Jul 25.

Abstract

Primary peripheral blood monocytes are responsible for the hematogenous dissemination of human cytomegalovirus (HCMV) following a primary infection. In order to facilitate viral spread, HCMV extends the naturally short 48-h lifespan of monocytes by stimulating a non-canonical activation of Akt during viral entry, which leads to the increased expression of a specific subset of antiapoptotic proteins. In this study, global analysis of the Akt signaling network showed HCMV induced a more robust activation of the entire network when compared to normal myeloid growth factors. Furthermore, we found a unique interplay between HCMV-activated Akt and the stress response transcription heat shock factor 1 (HSF1) that allowed for the synthesis of both cap- and internal ribosome entry site (IRES)-containing antiapoptotic mRNAs such as myeloid cell leukemia-1 (Mcl-1) and X-linked inhibitor of apoptosis (XIAP), respectively. As generally a switch from cap-dependent to IRES-mediated translation occurs during cellular stress, the ability of HCMV to concurrently drive both types of translation produces a distinct milieu of prosurvival proteins needed for the viability of infected monocytes. Indeed, we found inhibition of XIAP led to death of ∼99% of HCMV-infected monocytes while having minimal effect on the viability of uninfected cells. Taken together, these data indicate that the aberrant activation of the Akt network by HCMV induces the upregulation of a unique subset of antiapoptotic proteins specifically required for the survival of infected monocytes. Consequently, our study highlights the possibility of exploiting these virus-induced changes to prevent viral spread in immunocompromised patients at high-risk for HCMV exposure.

Keywords: Cytomegalovirus; Monocytes; Small-molecule inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line
  • Cell Survival
  • Cytomegalovirus / physiology*
  • HSP27 Heat-Shock Proteins / metabolism
  • Heat Shock Transcription Factors / metabolism
  • Heat-Shock Proteins
  • Humans
  • Molecular Chaperones
  • Monocytes / virology*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger
  • Signal Transduction*
  • Up-Regulation
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • HSF1 protein, human
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins
  • MCL1 protein, human
  • Molecular Chaperones
  • Myeloid Cell Leukemia Sequence 1 Protein
  • RNA, Messenger
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Proto-Oncogene Proteins c-akt