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Viruses encode specific proteins that modify the regulatory machinery of the infected cell, overcoming host antiviral defenses and creating an optimal environment for viral replication. Mechanistic studies of virus-host interactions have provided a unique window into the workings of the cell and the origins of human cancer. We are interested in the ways in which herpesviruses modulate cellular transcription factors involved in control of cell proliferation; studies that will expand our understanding of the mammalian cell cycle and the virus-mediated oncogenesis.We have focused on two important viral regulatoy proteins: VP16 from herpes simplex virus (HSV) and LANA from Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8).
VP16, a potent transcriptional activator encoded by HSV, targets a conserved cellular factor known as HCF-1. Using a temperature-sensitive cell line, we have shown that HCF-1 is required for progression through G1 phase of the cell cycle and acts as a coactivator for a variety of celluar transcription factors. To understand how HCF-1 promotes cell growth we are currently following two major directions: (i) the identification and analysis of other nuclear proteins that interact with HCF-1 or with HCF-2, a related protein identified in our lab and (ii) characterization of HCF function in the fruit fly Drosophila; an attractive model system that combines the power of genetics, biochemistry and developmental biology.
A second area under investigation in the lab is the role of KSHV in the development of Kaposi's sarcoma (KS), the leading tumor seen in AIDS patients and in the less common but more aggressive primary effusion lymphoma (PEL). We are interested in the establishment and maintenance of latent KSHV infection, focusing on the role of LANA in maintaining the viral genome during proliferation of the host cell. We also study the regulation of gene expression during reactivation focusing on viral factors that regulate gene transcription and post-transcriptional events.
These studies will provide new insight into the mechanisms behind the immortalization of latently-infected B cells and endothelial cells - the first step towards development of KS or PEL tumors.
Using homogeneous primary neuron cultures to study fundamental aspects of HSV-1 latency and reactivation
Kim, Ju Youn; Shiflett, Lora A; Linderman, Jessica A; Mohr, Ian; Wilson, Angus C. Using homogeneous primary neuron cultures to study fundamental aspects of HSV-1 latency and reactivation. Methods in molecular biology. 2014 ;1144:167-179 (970092)
Expression of Herpes Simplex Virus 1 MicroRNAs in Cell Culture Models of Quiescent and Latent Infection
Jurak, Igor; Hackenberg, Michael; Kim, Ju Youn; Pesola, Jean M; Everett, Roger D; Preston, Chris M; Wilson, Angus C; Coen, Donald M. Expression of Herpes Simplex Virus 1 MicroRNAs in Cell Culture Models of Quiescent and Latent Infection. Journal of virology. 2013 Dec 4;88(4):2337-2339 (836682)
Transient Reversal of Episome Silencing Precedes VP16-Dependent Transcription during Reactivation of Latent HSV-1 in Neurons
Kim, Ju Youn; Mandarino, Angelo; Chao, Moses V; Mohr, Ian; Wilson, Angus C. Transient Reversal of Episome Silencing Precedes VP16-Dependent Transcription during Reactivation of Latent HSV-1 in Neurons. PLoS pathogens. 2012 Feb 23;8(2):e1002540-e1002540 e1002540 (159845)
A primary neuron culture system for the study of herpes simplex virus latency and reactivation
Kobayashi, Mariko; Kim, Ju-Youn; Camarena, Vladimir; Roehm, Pamela C; Chao, Moses V; Wilson, Angus C; Mohr, Ian. A primary neuron culture system for the study of herpes simplex virus latency and reactivation. Journal of visualized experiments : JoVE. 2012 Apr 2;(62):?-? (164363)
Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor
Kobayashi, Mariko; Wilson, Angus C; Chao, Moses V; Mohr, Ian. Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor. Genes & development. 2012 Jul 15;26(14):1527-1532 (174034)