Kaposi's sarcoma (KS) is a multifocal vascular tumor of mixed cellular composition that is the most common neoplasm in patients with acquired immunodeficiency syndrome (AIDS). A new member of the herpesvirus group, Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), has been consistently identified in KS, body cavity-based lymphomas (BCBLs) and some forms of multicentric Castleman's disease (MCD). Analysis of the genomic sequences of rhesus monkey rhadinovirus (RRV) has revealed that RRV is very closely related to Kaposi's sarcoma-associated herpesvirus. RRV naturally infects rhesus macaques and has been shown to induce B-cell hyperplasia in the context of infection with simian immunodeficiency virus (SIV) in macaques. We have studied the transformation properties of the RRV R1 and the KSHV K1 viral oncogenes. We have shown that R1 and K1 are functional homologs capable of inducing transformation, and cellular activation and proliferation events. We propose to dissect the molecular mechanisms by which K1 and R1 cause transformation. These studies involve analyzing the regulation of cellular signal transduction and cellular apoptotic pathways by these viral oncogenes. Detailed functional studies of these proteins will be performed in order to understand the specific role of R1 and K1 in viral replication and oncogenic transformation. We will utilize the RRV genetic system to construct recombinant rhesus rhadinoviruses. We have constructed a recombinant RRVdeltaRl virus for this purpose and will use it to evaluate the relative importance and functional contribution of R1 to viral replicative capacity, tropism, and cellular gene expression. A genetic complementation assay will be performed using the RRVdeltaRI virus and a panel of wild-type and mutant K1 and R1 proteins to map the functional domains of K1 and R1 that are biologically important for viral replication. The proposed study is directed towards understanding the molecular mechanisms of K1 signaling and transformation, and hence the biological role of K1 in KSHV-associated pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA096500-05S1
Application #
7239440
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Ogunbiyi, Peter
Project Start
2002-07-15
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$39,480
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Anders, Penny M; Montgomery, Nathan D; Montgomery, Stephanie A et al. (2018) Human herpesvirus-encoded kinase induces B cell lymphomas in vivo. J Clin Invest 128:2519-2534
Wong, Jason P; Damania, Blossom (2017) Modulation of oncogenic signaling networks by Kaposi's sarcoma-associated herpesvirus. Biol Chem 398:911-918
Zhang, Zhigang; Chen, Wuguo; Sanders, Marcia K et al. (2016) The K1 Protein of Kaposi's Sarcoma-Associated Herpesvirus Augments Viral Lytic Replication. J Virol 90:7657-66
Ma, Zhe; Damania, Blossom (2016) Editorial: NLRP3: immune activator or modulator? J Leukoc Biol 99:641-3
Bhatt, Aadra Prashant; Wong, Jason P; Weinberg, Marc S et al. (2016) A viral kinase mimics S6 kinase to enhance cell proliferation. Proc Natl Acad Sci U S A 113:7876-81
Damania, Blossom (2016) A Virological Perspective on Cancer. PLoS Pathog 12:e1005326
Ma, Zhe; Damania, Blossom (2016) The cGAS-STING Defense Pathway and Its Counteraction by Viruses. Cell Host Microbe 19:150-8
Dittmer, Dirk P; Damania, Blossom (2016) Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest 126:3165-75
Anders, Penny M; Zhang, Zhigang; Bhende, Prasana M et al. (2016) The KSHV K1 Protein Modulates AMPK Function to Enhance Cell Survival. PLoS Pathog 12:e1005985
Johnson, Amy R; Qin, Yuanyuan; Cozzo, Alyssa J et al. (2016) Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5:506-526

Showing the most recent 10 out of 64 publications