Kaposi's sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi's sarcoma (KS), the most common neoplasm in untreated HIV-1 infected individuals. In China where there is an increase in the number of HIV-1 infected individuals, it is likely that KS will also become a major problem in these patients as their disease progresses. KSHV infection goes through lytic and latent phases and viral lytic replication plays an essential role in the development of KS tumors. Our data suggests that innate immunity, through the interferon pathway, is involved in suppressing lytic viral replication. Our findings indicate that upon KSHV infection, the host responds by suppression of lytic gene expression through the interferon responding factor 7 (IRF-7). IRF-7 competes for promoter binding sites with an essential viral regulatory protein known as RTA (replication and transcription activator) which alone is sufficient to initiate lytic replication by activating downstream lytic genes. Moreover, it is likely that post-translational modification and activation of IRF-7, such as phosphorylation or sumoylation may also be involved in the repression of RTA. Our overall objective for the proposed study is to further understand how IRF-7 antagonizes RTA activation pathways, whether activation and modification of IRF-7 are required, and to identify and characterize the viral and cellular factors involved. We hypothesize that in KSHV infected cells, newly activated IRF-7 competes with the viral RTA to prevent RTA's binding and activation of viral lytic gene expression, and thereby inhibits viral replication. To substantiate this hypothesis, the following aims are proposed:
Aim 1 : to characterize the molecular interplay between IRF-7 and RTA.
Aim 2 : to understand how IRF-7 is stimulated, modified and involved in repression of lytic viral replication.
Aim 3 : To investigate the role of IRF-7 in the regulation of KSHV lytic replication during infection. A more complete understanding of the mechanisms that control and suppress viral replication could lead to development of preventive strategies against KS in HIV-1 infected individuals.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Research Project (R01)
Project #
5R01TW007294-04
Application #
7388884
Study Section
Special Emphasis Panel (ZRG1-ICP-2 (50))
Program Officer
Liu, Xingzhu
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$51,202
Indirect Cost
Name
Nankai University
Department
Type
DUNS #
529664864
City
Tianjin
State
Country
China
Zip Code
30007-1