Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons.
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.
Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Vladimir
V
Camarena
Mariko
M
Kobayashi
Ju Youn
JY
Kim
Pamela
P
Roehm
Rosalia
R
Perez
James
J
Gardner
Angus C
AC
Wilson
Ian
I
Mohr
Moses V
MV
Chao
D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000821:virology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction; D014709:Vero Cells; D014775:Virus Activation; D017735:Virus Latency
D009414:Nerve Growth Factors; C000631429:PDK1 protein, human; C000631434:Pdk1 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D058543:Class Ia Phosphatidylinositol 3-Kinase; D058539:Phosphatidylinositol 3-Kinase; D020917:Receptor, trkA; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt