Investigating the Role of p53 in Herpes Simplex Virus - 1 Replication
AffiliationThe University of Arizona College of Medicine – Phoenix
MeSH SubjectsBasic Sciences
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PublisherThe University of Arizona.
DescriptionA Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
AbstractHerpes simplex virus 1 (HSV-1) is a common human virus that can cause a variety of pathologies, including oral lesions and invariably fatal encephalitis. As there is currently no cure for HSV-1 infection, worldwide morbidity and mortality rates remain high. HSV-1 replication is under intricate control by both viral and cellular factors that dictate whether the virus undergoes productive lytic replication or enters a state of latency during which there is decreased viral gene expression and virus production. The intricate mechanisms that determine the fate of the virus are not completely understood. p53, the well-known tumor suppressor gene, is involved in various cellular responses to stress, such as viral infection. We hypothesized that p53 plays a role in the establishment of HSV-1 latency by negatively regulating HSV-1 replication through repression of viral gene expression via the ATM/ATR damage response pathway leading to expression of p53 and regulation of gene expression via p53 response elements (RE). Viral yields were determined for HSV-1 strain KOS grown on HCT116 wild-type (p53 +/+) and HCT116 p53-deficient (p53 -/-) cells at a multiplicity of infection (MOI) of 1 and at 72 hours post-infection, with the prediction that the viral titer would be higher for the virus derived from the HCT116 p53-deficient cells. Our results demonstrate that there is no significant difference in HSV-1 titer between p53-deficient cells and wildtype cells under these conditions. This suggests that p53 does not play a vital role in promoting HSV-1 latency overall; rather, p53 may exert both positive and negative effects on HSV-1 replication at varying points in time without favoring one cycle over another. Future research, such as determining viral yield harvested from cells in which the levels of p53 have been increased by both overexpression and the use of pharmacological agents to stabilize endogenous p53, should be conducted to further elucidate these complexities.