Many viruses infect the nervous system, where they either multiply or become silent in neurons. The decision to become latent versus lytic is not well understood. One prevalent virus in human population is Herpes simplex virus-1 (HSV-1) that establishes a life-long latent infection in peripheral neurons where productive replication is suppressed. When HSV is activated and multiplied, a range of diseases can ensue, which may lead to blisters or to more serious consequences, such inflammation in the brain or blindness. One factor that has hindered the development of new therapies against HSV latent state is the lack of understanding of cellular mechanisms that regulate the latent state. In our studies, we improved an in vitro system for viral latency in primary neurons to investigate the factors that keep HSV from multiplying. We find that nerve growth factor is essential to keep the virus latent. We show that continuous signaling through the PI3-kinase (PI3-K) pathway triggered by NGF-binding to the TrkA receptor tyrosine kinase (RTK) is instrumental to maintain latent HSV-1 in primary neuron cultures. Activity of the PI3-K p110α catalytic subunit, but not the β or δ isoforms, is specifically required to activate PDK1 and sustain latency. Disrupting this pathway, even transiently, using chemical inhibitors or RNA interference leads to reactivation. Surprisingly, EGF and GDNF, two other growth factors capable of activating PI3-K and PDK1, differ from NGF in their ability to persistently activate Akt and do not fully support HSV-1 latency. Thus the duration and intensity of RTK-signaling are critical parameters imposed by the host to regulate the HSV-1 latent-lytic switch. This work sheds light on how latency is regulated by growth factors in the nervous system, which in turn could help to develop new targeted therapies against HSV activation.
|Advisor:||Chao, Moses V., Mohr, Ian J.|
|Commitee:||Franke, Thomas F., Greene, Lloyd, Wilson, Angus C., Ziff, Edward|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 72/01, Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Virology|
|Keywords:||Herpes simplex virus, Nerve growth factors, PI3-kinase, Reactivation, Viral latency|
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