Recurrent infections with herpes simplex viruses (HSV) are a significant clinical problem. Fundamental to understanding the nature of recurrent herpetic disease is determining precisely how HSV alternates between the two phases of its dual life cycle, latency and reactivation of productive infection. The LAT-ICP0 locus plays a central role in the regulation of HSV-1 latency and reactivation. The genes that encode for the latency-associated transcripts (LATs) and infected cell polypeptide 0 (ICP0) form a continuous locus in the repeated regions of the HSV genome. Specifically, the LAT and ICP0 genes lie on opposite strands of HSV-1's double-stranded DNA genome and share a significant overlap. Thus, the abundant LATs can hybridize to 0.75 kilobases of complementary sequence in ICP0 mRNA. While the antisense arrangement of the LAT-ICP0 locus has long been recognized, the hypothesis that LAT RNAs serve as """"""""antisense repressors"""""""" of ICP0 gene expression has not been rigorously analyzed. The juxtaposition of the LAT and ICP0 genes mirrors their opposing roles in latency. While LAT RNAs facilitate the maintenance of HSV latency, expression of ICP0 is necessary and sufficient to induce HSV-1 reactivation. Conversely, failure to express ICP0 is highly conducive to HSV genomes entering a transcriptionally repressed state. Thus, antisense repression of ICP0 mRNA translation is one mechanism by which LATs may facilitate the maintenance of latency. The goal of this research proposal is to evaluate the concept that LAT RNAs and ICP0 form a pair of mutually dependent, opposite regulators that are the yin and yang of HSV latency. Specifically, genetic evidence will be obtained to test the hypothesis that """"""""All viral proteins that induce HSV-1 reactivation in the trigeminal ganglion cell culture model achieve this phenotype via (a) induction of ICP0, (b) suppression of LAT transcription, or (c) both.""""""""

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051414-04
Application #
6847430
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Beisel, Christopher E
Project Start
2003-08-01
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
4
Fiscal Year
2005
Total Cost
$247,625
Indirect Cost
Name
Montana State University - Bozeman
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
Halford, William P; PĆ¼schel, Ringo; Rakowski, Brandon (2010) Herpes simplex virus 2 ICP0 mutant viruses are avirulent and immunogenic: implications for a genital herpes vaccine. PLoS One 5:e12251
Liu, Mingyu; Rakowski, Brandon; Gershburg, Edward et al. (2010) ICP0 antagonizes ICP4-dependent silencing of the herpes simplex virus ICP0 gene. PLoS One 5:e8837
Liu, Mingyu; Schmidt, Edward E; Halford, William P (2010) ICP0 dismantles microtubule networks in herpes simplex virus-infected cells. PLoS One 5:e10975
Carr, Daniel J J; Austin, Bobbie A; Halford, William P et al. (2009) Delivery of Interferon-gamma by an adenovirus vector blocks herpes simplex virus Type 1 reactivation in vitro and in vivo independent of RNase L and double-stranded RNA-dependent protein kinase pathways. J Neuroimmunol 206:39-43
Austin, Bobbie Ann; Halford, William P; Williams, Bryan R G et al. (2007) Oligoadenylate synthetase/protein kinase R pathways and alphabeta TCR+ T cells are required for adenovirus vector: IFN-gamma inhibition of herpes simplex virus-1 in cornea. J Immunol 178:5166-72
Halford, William P; Weisend, Carla; Grace, Jennifer et al. (2006) ICP0 antagonizes Stat 1-dependent repression of herpes simplex virus: implications for the regulation of viral latency. Virol J 3:44
Halford, William P; Halford, Keith J; Pierce, Amy T (2005) Mathematical analysis demonstrates that interferons-beta and -gamma interact in a multiplicative manner to disrupt herpes simplex virus replication. J Theor Biol 234:439-54
Halford, William P; Maender, Jennifer L; Gebhardt, Bryan M (2005) Re-evaluating the role of natural killer cells in innate resistance to herpes simplex virus type 1. Virol J 2:56
Gebhardt, Bryan M; Halford, William P (2005) Evidence that spontaneous reactivation of herpes virus does not occur in mice. Virol J 2:67