: Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV-8) is an etiologic agent of Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). HHV-8 remains latent in the majority of tumor cells, but undergoes reactivation in a small percentage of tumor cells in KS. A viral immediate-early gene product, Rta (lytic replication and transcription activator), has been found to be sufficient and necessary to disrupt latency and initiate viral lytic gene expression in PEL cell lines latently infected by HHV-8. Rta also activates the expression of virally encoded homologues of interleukin 6 (IL-6) and macrophage inflammatory protein (MIP) lalpha, which are believed to play important roles in the pathogenesis of KS, MCD and PEL. The dynamic balance between latency and lytic replication plays a critical role in determining the pathogenic outcome of a viral infection. Therefore, it is critical for us to understand the mechanism that controls the switch between latency and lytic replication. Our initial finding of the pivotal role of Rta in the HHV-8 life cycle warrants further studies of the structure and function of Rta. Current data suggest the hypothesis that Rta activates viral lytic replication by trans-activating gene expression in an ordered cascade. Our objective is to dissect this cascade and the mechanism by which Rta activates the transcription of downstream genes. Accordingly, the Specific Aims of this proposal are to: 1. Identify genes directly activated by Rta and define the sequence binding specificity of Rta; 2. Define the amino acid sequences of Rta required for its trans-activation function. Understanding the mechanism of the switch from latency to lytic replication will aid in the development of new therapeutic strategies for diseases associated with HHV-8 infection. By regulating the expression and/or function of Rta, we can either suppress viral replication to inhibit the spread of viral infection or induce viral lytic replication to destroy infected tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA091791-05S1
Application #
7034805
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ogunbiyi, Peter
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
5
Fiscal Year
2005
Total Cost
$46,489
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dai, Xinghong; Gong, Danyang; Lim, Hanyoung et al. (2018) Structure and mutagenesis reveal essential capsid protein interactions for KSHV replication. Nature 553:521-525
Gong, Danyang; Dai, Xinghong; Xiao, Yuchen et al. (2017) Virus-Like Vesicles of Kaposi's Sarcoma-Associated Herpesvirus Activate Lytic Replication by Triggering Differentiation Signaling. J Virol 91:
York, Autumn G; Williams, Kevin J; Argus, Joseph P et al. (2015) Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling. Cell 163:1716-29
Feng, Jiaying; Gong, Danyang; Fu, Xudong et al. (2015) M1 of Murine Gamma-Herpesvirus 68 Induces Endoplasmic Reticulum Chaperone Production. Sci Rep 5:17228
Dai, Xinghong; Gong, Danyang; Xiao, Yuchen et al. (2015) CryoEM and mutagenesis reveal that the smallest capsid protein cements and stabilizes Kaposi's sarcoma-associated herpesvirus capsid. Proc Natl Acad Sci U S A 112:E649-56
Sun, Chenglong; Schattgen, Stefan A; Pisitkun, Prapaporn et al. (2015) Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection. J Immunol 194:1819-31
Wong-Ho, Elaine; Wu, Ting-Ting; Davis, Zoe H et al. (2014) Unconventional sequence requirement for viral late gene core promoters of murine gammaherpesvirus 68. J Virol 88:3411-22
Gong, Danyang; Wu, Nicholas C; Xie, Yafang et al. (2014) Kaposi's sarcoma-associated herpesvirus ORF18 and ORF30 are essential for late gene expression during lytic replication. J Virol 88:11369-82
Feng, Jun; De Jesus, Paul D; Su, Victoria et al. (2014) RIOK3 is an adaptor protein required for IRF3-mediated antiviral type I interferon production. J Virol 88:7987-97
Ning, Shaoyang; Xu, Hongquan; Al-Shyoukh, Ibrahim et al. (2014) An application of a Hill-based response surface model for a drug combination experiment on lung cancer. Stat Med 33:4227-36

Showing the most recent 10 out of 49 publications