Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons

Cell Host Microbe. 2010 Oct 21;8(4):320-30. doi: 10.1016/j.chom.2010.09.007.

Abstract

Herpes simplex virus-1 (HSV-1) establishes life-long latency in peripheral neurons where productive replication is suppressed. While periodic reactivation results in virus production, the molecular basis of neuronal latency remains incompletely understood. Using a primary neuronal culture system of HSV-1 latency and reactivation, we show that continuous signaling through the phosphatidylinositol 3-kinase (PI3-K) pathway triggered by nerve growth factor (NGF)-binding to the TrkA receptor tyrosine kinase (RTK) is instrumental in maintaining latent HSV-1. The PI3-K p110α catalytic subunit, but not the β or δ isoforms, is specifically required to activate 3-phosphoinositide-dependent protein kinase-1 (PDK1) and sustain latency. Disrupting this pathway leads to virus reactivation. EGF and GDNF, two other growth factors capable of activating PI3-K and PDK1 but that differ from NGF in their ability to persistently activate Akt, do not fully support HSV-1 latency. Thus, the nature of RTK signaling is a critical host parameter that regulates the HSV-1 latent-lytic switch.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Chlorocebus aethiops
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism
  • Herpesvirus 1, Human / physiology*
  • Nerve Growth Factors / metabolism*
  • Neurons / metabolism
  • Neurons / virology*
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptor, trkA / metabolism*
  • Signal Transduction
  • Vero Cells
  • Virus Activation
  • Virus Latency*

Substances

  • Nerve Growth Factors
  • PDK1 protein, human
  • Pdk1 protein, rat
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • RNA, Small Interfering
  • Class Ia Phosphatidylinositol 3-Kinase
  • Phosphatidylinositol 3-Kinase
  • Receptor, trkA
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt