Herpesviruses are ubiquitous and are responsible for significant human mortality and suffering both in terms of initial infections and (even more so) recurrences. In addition, with increasing occurrences of immunosuppressive disorders, a corresponding increase in the frequency of clinically significant initial and latent herpesvirus infections arise. Therefore, the long-term objective of this project is to gain a functional understanding of the herpesvinis-encoded genes involved in latency and reactivation - knowledge that is fundamental to the rational design of interventive therapies. We have identified a region of the genome termed the """"""""reactivation critical region"""""""" (rcr) that is required for epinephrine-induced reactivation. The primary focus of this proposal is to characterize the functional role sequence elements in the rcr of the Herpes simplex virus type 1 (HSV- 1) genome play in reactivation of infections latent in sensory ganglia neurons. The overriding hypothesis of this study is that the HSV rcr facilitates reactivation by regulating gene expression from the latent genome allowing the initiation of acute gene expression during reactivation. Using a molecular genetic approach involving specifically engineered viral recombinants, we will follow the transcriptional and replicative processes of HSV- 1 reactivation in the rabbit cornea-epinephrine model to link viral genetics with processes in animals. Specifically, the proposed studies will test three potential mechanisms by which the rcr functions to facilitate reactivation: a) the rcr acts as a modulator of transcription which facilitates reactivation by regulating the expression of LAT, ICPO and/or ICP4, b) the rcr is a target of methylation and/or cellular factors that regulate transcription during latency and reactivation, and c) the rcr acts as a non-coding functional RNA that regulates gene expression via a dosage compensation-like mechanism. These three mechanisms are not mutually exclusive and it is likely an interplay between these regulatory elements is necessary for the maintenance of and reactivation from latency. This work will lead to the identification of viral target(s) of host factors that communicate stress stimuli leading to reactivation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048633-02
Application #
6511391
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Beisel, Christopher E
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$266,649
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Watson, Zachary L; Washington, Shannan D; Phelan, Dane M et al. (2018) In Vivo Knockdown of the Herpes Simplex Virus 1 Latency-Associated Transcript Reduces Reactivation from Latency. J Virol 92:
Washington, Shannan D; Edenfield, Samantha I; Lieux, Caroline et al. (2018) Depletion of the insulator protein CTCF results in HSV-1 reactivation in vivo. J Virol :
Morse, Alison M; Calabro, Kaitlyn R; Fear, Justin M et al. (2017) Reliable Detection of Herpes Simplex Virus Sequence Variation by High-Throughput Resequencing. Viruses 9:
Watson, Zachary L; Ertel, Monica K; Lewin, Alfred S et al. (2016) Adeno-associated Virus Vectors Efficiently Transduce Mouse and Rabbit Sensory Neurons Coinfected with Herpes Simplex Virus 1 following Peripheral Inoculation. J Virol 90:7894-901
Messer, Harald G P; Jacobs, Derek; Dhummakupt, Adit et al. (2015) Inhibition of H3K27me3-specific histone demethylases JMJD3 and UTX blocks reactivation of herpes simplex virus 1 in trigeminal ganglion neurons. J Virol 89:3417-20
Yang, Yajie; Fear, Justin; Hu, Jianhong et al. (2014) Leveraging biological replicates to improve analysis in ChIP-seq experiments. Comput Struct Biotechnol J 9:e201401002
Watson, Zachary; Dhummakupt, Adit; Messer, Harald et al. (2013) Role of polycomb proteins in regulating HSV-1 latency. Viruses 5:1740-57
Bertke, Andrea S; Apakupakul, Kathleen; Ma, AyeAye et al. (2012) LAT region factors mediating differential neuronal tropism of HSV-1 and HSV-2 do not act in trans. PLoS One 7:e53281
Bloom, David C; Giordani, Nicole V; Kwiatkowski, Dacia L (2010) Epigenetic regulation of latent HSV-1 gene expression. Biochim Biophys Acta 1799:246-56
Kwiatkowski, Dacia L; Thompson, Hilary W; Bloom, David C (2009) The polycomb group protein Bmi1 binds to the herpes simplex virus 1 latent genome and maintains repressive histone marks during latency. J Virol 83:8173-81

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