Once an individual is infected with herpes simplex virus (HSV), the virus establishes a latent infection in sensory neurons. Periodically, various stimuli may induce lytic reactivation resulting in mild recurrent lesions to more severe disease. The factors which determine the establishment of latency and reactivation are poorly understood. However, the regulation of this latency-reactivation cycle is dependent upon the components which regulate the expression of the IE genes. The critical component of this regulatory process is HCF-1. Analyses of this protein in a mouse model have shown that the protein is specifically sequestered in the cytoplasm of sensory neurons and rapidly transported to the nucleus in response to reativation stimuli. Recent work has resulted in the establishment of a primary sensory neuronal cell culture which allowed for the specific localization of HCF-1 in the cytoplasm. Additional studies have determined that the nuclear transport of HCF-1 in latently infected neurons correlates with viral reactivation and that HCF-1 is rapidly recruited to the promoters of the viral IE genes upon initiation of reactivation. Data also suggests that HCF-1 modulates viral chromatin structure to initiate viral reactivation from latency. In 2012, studies in animal model systems of viral reactivation have demonstrated the utility of small molecule inhibitors of HCF-1 associated chromatin modulation components to block viral reactivation from latency.

Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2012
Total Cost
$257,315
Indirect Cost
City
State
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Kristie, Thomas M (2015) Dynamic modulation of HSV chromatin drives initiation of infection and provides targets for epigenetic therapies. Virology 479-480:555-61
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Arbuckle, Jesse H; Kristie, Thomas M (2014) Epigenetic repression of herpes simplex virus infection by the nucleosome remodeler CHD3. MBio 5:e01027-13
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Liang, Yu; Quenelle, Debra; Vogel, Jodi L et al. (2013) A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency. MBio 4:e00558-12

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