Productive infection by herpes simplex virus (HSV) is stimulated by the virally-encoded transcription factor VP16, which associates with the cellular transcription factor HCF-1 to form a multiprotein-DNA complex on each of the five viral immediate-early (IE) gene promoters. Failure of HSV to express sufficient levels of IE gene products may lead to the establishment of a latent infection in appropriate cell types such as sensory neurons. The importance of HCF-1 to the viral productive cycle is most clearly demonstrated by infection of cells with a conditionally inactivated version of HCF-1. This results in a significant delay in viral gene expression and severely reduced virus yield. Dr. Wilson proposes that differences in the activity or localization of HCF-1 in sensory neurons contribute to the establishment or maintenance of viral latency. In these cells, HCF-1 is found predominantly in cytoplasm, a striking contrast to most other cell types where HCF-1 is predominantly nuclear. Signals that promote reactivation also trigger a rapid relocalization of HCF-1 to the nucleus. To this end, they have identified a novel HCF-1 associated protein with characteristics of a nucleocytoplasmic shuttle factor that may be responsible for the dynamic localization of HCF-1 in neurons. Regulation of HCF-1 localization may also be important in other contexts. HCF-1 is required for transcriptional activation by a number of DNA-binding proteins and loss of HCF-1 leads to an arrest in G1 phase of the cell cycle.
The aims of this proposal are to:
(Aim 1) understand how VP16 and the novel shuttle protein (designated HPIP) selectively target HCF-1 rather than the close-relative HCF-2;
(Aim 2) demonstrate suppression of IE gene expression by the candidate shuttle proteins (HPIP) and establish its mode of action in sensory neurons and other cell types;
and (Aim 3) test the hypothesis that HCF-1 stimulates IE gene activation by interacting with additional transcription factors bound to sites flanking the VP16-responsive elements in each IE promoter. The investigator suggests that the pivotal role of HCF-1 in initiating viral IE gene expression represents an important target for the design of new therapeutic strategies to combat human diseases that arise from HSV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM061139-01A1
Application #
6283496
Study Section
Virology Study Section (VR)
Program Officer
Tompkins, Laurie
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
1
Fiscal Year
2001
Total Cost
$271,178
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Kim, Ju Youn; Mandarino, Angelo; Chao, Moses V et al. (2012) Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons. PLoS Pathog 8:e1002540
Wilson, Angus C; Mohr, Ian (2012) A cultured affair: HSV latency and reactivation in neurons. Trends Microbiol 20:604-11
Kobayashi, Mariko; Wilson, Angus C; Chao, Moses V et al. (2012) Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor. Genes Dev 26:1527-32
Kobayashi, Mariko; Kim, Ju-Youn; Camarena, Vladimir et al. (2012) A primary neuron culture system for the study of herpes simplex virus latency and reactivation. J Vis Exp :
Xi, Xiangmei; Persson, Linda M; O'Brien, Michael W et al. (2012) Cooperation between viral interferon regulatory factor 4 and RTA to activate a subset of Kaposi's sarcoma-associated herpesvirus lytic promoters. J Virol 86:1021-33
Persson, Linda M; Wilson, Angus C (2010) Wide-scale use of Notch signaling factor CSL/RBP-Jkappa in RTA-mediated activation of Kaposi's sarcoma-associated herpesvirus lytic genes. J Virol 84:1334-47
Camarena, Vladimir; Kobayashi, Mariko; Kim, Ju Youn et al. (2010) Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons. Cell Host Microbe 8:320-30
Misaghi, Shahram; Ottosen, Søren; Izrael-Tomasevic, Anita et al. (2009) Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol 29:2181-92
Pearce, Michael; Matsumura, Satoko; Wilson, Angus C (2005) Transcripts encoding K12, v-FLIP, v-cyclin, and the microRNA cluster of Kaposi's sarcoma-associated herpesvirus originate from a common promoter. J Virol 79:14457-64
Wong, Lai-Yee; Wilson, Angus C (2005) Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induces a strong bend on binding to terminal repeat DNA. J Virol 79:13829-36

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