Herpes simplex virus type 1 (HSV-1) is a human pathogen, infecting about 90% of the human population during their lifetime. Like other herpesviruses, HSV-1 engages in one of two types of infection, lytic or latent, depending on cell types. In permissive cells such as the epithelial cells that line mucosal surfaces, HSV-1 replicates to produce a new generation of infectious virions in a process is called lytic infection. HSV-1 latently infects peripheral neurons, where the viral genome stays in a semi-dormant state in the nucleus without generating virions and without expressing viral proteins. Various stimuli can trigger latent HSV-1 to (re)engage in lytic replication; this process is called `reactivation.' This ability to hide and reactivate enables HSV-1 to permanently colonize the host and makes the virus very difficult to eradicate.
Despite decades of study, the molecular basis of reactivation remains enigmatic due to a lack of suitable model systems, intrinsic differences between existing models, and limitations in the methodologies that can be used. Using a newly improved in vitro culture model involving pure cultures of sympathetic neurons that permit manipulations at the molecular level and real-time monitoring of reactivation, we have begun to characterize the initial response of the latent virus to a defined reactivation cue. In this system, continuous nerve growth factor (NGF) signaling is required to maintain latency and can be blocked using a PI3-kinase inhibitor to elicit reactivation. After a delay, HSV-1 genes are transcribed in two waves or phases, termed Phase I and Phase II. This is radically different from de novo infections of permissive cells. Phase I and Phase II differ from each other in several aspects including the reliance on the viral protein VP16, which is made in Phase I but is not required until Phase II. The sub-cellular localization of VP16 is an important part of the regulatory mechanism, and parallels the dynamic localization of the essential cellular co-factor HCF-1. Studies described in this thesis offer new insights into the initial events that occur during reactivation and suggest new ways to prevent or manipulate HSV-1 latency.
|Advisor:||Wilson, Angus C.|
|Commitee:||Borowiec, James, Mohr, Ian, Tanese, Naoko|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 74/07(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Microbiology, Virology|
|Keywords:||Hcf-1, Herpes simplex virus type 1, Hsv-1, Latency, Reactivation, Vp16|
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