KSHV latency control is stringently regulated by the interplay of two critical viral proteins that are expressed temporally during the life cycle of the virus. The human gammaherpesviruses KSHV and EBV both are predominantly latent in the infected cell although there are some levels of reactivation that persists in the population. In KSHV the immediate early transactivator Rta is packaged in the virion particle and is responsible for activating the major latent promoter responsible for transcription of the latent genes which include the latency associated nuclear antigen (LANA). Once LANA is expressed it functions as a multifaceted molecule which is responsible for the maintenance of the viral genome in the infected cells as well as the transcription regulation of Rta function which has been shown to autoactivate its own promoter during lytic replication. In esence these controls establish a finely tuned feedback loop for control of KSHV latency. In this application we will investigate the role of critical viral antigens responsible for latency control and determine the level of post-translational modification that is necessary for these regulatory events. We will also utilize a proteomic approach with recombinant KSHV cloned into the bacmid vector with wild type KSHV and a Rta knockout virus to identify the cellular components of the regulatory events. We will also determine the level of cellular control of the Rta promoter by determining the transcription modulators that are involved in chromatin remodeling at the specific sites targeted by the viral antigensto control latency and determine the extent at which the signaling pathway is utilized to establish latency and contribute to cell proliferation of KSHV infected cells. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067037-03
Application #
7449608
Study Section
Special Emphasis Panel (ZRG1-AARR-A (94))
Program Officer
Beisel, Christopher E
Project Start
2006-07-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$337,560
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cai, Qiliang; Xiao, Bingyi; Si, Huaxin et al. (2012) Kaposi's sarcoma herpesvirus upregulates Aurora A expression to promote p53 phosphorylation and ubiquitylation. PLoS Pathog 8:e1002566
Cai, Qiliang; Guo, Yi; Xiao, Bingyi et al. (2011) Epstein-Barr virus nuclear antigen 3C stabilizes Gemin3 to block p53-mediated apoptosis. PLoS Pathog 7:e1002418
Gao, Jianming; Cai, Qiliang; Lu, Jie et al. (2011) Upregulation of cellular Bcl-2 by the KSHV encoded RTA promotes virion production. PLoS One 6:e23892
Cai, Qiliang; Verma, Suhbash C; Kumar, Pankaj et al. (2010) Hypoxia inactivates the VHL tumor suppressor through PIASy-mediated SUMO modification. PLoS One 5:e9720
Cai, Qiliang; Verma, Subhash C; Choi, Ji-Young et al. (2010) Kaposi's sarcoma-associated herpesvirus inhibits interleukin-4-mediated STAT6 phosphorylation to regulate apoptosis and maintain latency. J Virol 84:11134-44
Cai, Qiliang; Verma, Suhbash C; Lu, Jie et al. (2010) Molecular biology of Kaposi's sarcoma-associated herpesvirus and related oncogenesis. Adv Virus Res 78:87-142
Xiao, Bingyi; Verma, Subhash C; Cai, Qiliang et al. (2010) Bub1 and CENP-F can contribute to Kaposi's sarcoma-associated herpesvirus genome persistence by targeting LANA to kinetochores. J Virol 84:9718-32
Cai, Qiliang; Robertson, Erle S (2010) Ubiquitin/SUMO modification regulates VHL protein stability and nucleocytoplasmic localization. PLoS One 5:
Kumar, Pankaj; Murakami, Masanao; Kaul, Rajeev et al. (2009) Deregulation of the cell cycle machinery by Epstein-Barr virus nuclear antigen 3C. Future Virol 4:79-91
Si, Huaxin; Verma, Subhash C; Lampson, Michael A et al. (2008) Kaposi's sarcoma-associated herpesvirus-encoded LANA can interact with the nuclear mitotic apparatus protein to regulate genome maintenance and segregation. J Virol 82:6734-46

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