Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma (KS) and two lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The risk for KS is greatly increased in HIV-infected individuals and this is the most common malignancy in several countries in subequatorial Africa. KS is largely incurable with current therapeutic options. While KS is caused by KSHV, no effective virus-specific therapies exist. A better understanding of the pathobiology of KSHV infection, and robust animal models are essential for developing preventive and therapeutic strategies. Current animal models rely on expression of single viral genes in broad cellular populations, use of related animal viruses (none of which lead to KS or PEL-like disease), xenografts consisting of human tumor cells injected into immunodeficient mice, infection of humanized mice (with no resulting pathology), or implantation of cells previously infected or transfected in vitro. All of these animal models have significant limitation. Therefore, the goal of this project is to generate better mouse models to evaluate the effect of KSHV latent viral genes in vivo when selectively expressed in the specific cellular compartments that comprise the tumor cells in PEL and KS, namely B cells and endothelial cells. The majority of the cells in KSHV-associated tumors express only a few latent viral genes, although a very small and variable number of cells may also express some lytic genes. Conditional knock-in mice expressing the latent viral gene vFLIP in two different B cell subsets, all CD19+ cells or germinal center B cells, develop lymphadenopathies with features of MCD and tumors of B cell origin with long latency. We propose to extend these studies through the following specific aims: 1) discover complementing cellular and viral genetic events in vFLIP-mediated lymphomagenesis;2) develop and characterize mice expressing inducible vFLIP in endothelial cells;and 3) determine the effect of expression of the entire KSHV latency locus in endothelial cells, and assess the contribution of vGPCR expression in rare scattered cells. Through these aims, we anticipate developing mouse models that resemble human disease, which will be useful for a deeper understanding of the mechanisms of KSHV pathogenesis, and testing novel therapeutic approaches.

Public Health Relevance

The Kaposi's sarcoma herpesvirus (KSHV;also called human herpesvirus 8 or HHV-8), causes several types of cancer, including Kaposi's sarcoma, the most common cancer in several countries in Africa and more likely to occur in individuals with AIDS. KSHV does not infect mice, and all current mouse models have their limitations. We will develop new mouse models by expressing relevant viral products in specific cellular compartments, which will be useful to understand disease pathogenesis and develop new treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA103646-06A1
Application #
8410804
Study Section
Special Emphasis Panel (ZRG1-AARR-K (02))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2003-07-01
Project End
2017-06-30
Budget Start
2012-09-04
Budget End
2013-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$328,499
Indirect Cost
$134,121
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Totonchy, Jennifer; Osborn, Jessica M; Chadburn, Amy et al. (2018) KSHV induces immunoglobulin rearrangements in mature B lymphocytes. PLoS Pathog 14:e1006967
Ruder, Barbara; Murtadak, Vinay; St├╝rzl, Michael et al. (2018) Chronic intestinal inflammation in mice expressing viral Flip in epithelial cells. Mucosal Immunol 11:1621-1629
Nayar, Utthara; Sadek, Jouliana; Reichel, Jonathan et al. (2017) Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies. J Clin Invest 127:2066-2080
Giulino-Roth, Lisa; van Besien, Herman J; Dalton, Tanner et al. (2017) Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma. Mol Cancer Ther 16:1779-1790
Totonchy, Jennifer; Cesarman, Ethel (2016) Does persistent HIV replication explain continued lymphoma incidence in the era of effective antiretroviral therapy? Curr Opin Virol 20:71-77
Rodina, Anna; Wang, Tai; Yan, Pengrong et al. (2016) The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538:397-401
Liu, Wen-Hsien; Kang, Seung Goo; Huang, Zhe et al. (2016) A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells. J Exp Med 213:1901-19
Ballon, Gianna; Akar, Gunkut; Cesarman, Ethel (2015) Systemic expression of Kaposi sarcoma herpesvirus (KSHV) Vflip in endothelial cells leads to a profound proinflammatory phenotype and myeloid lineage remodeling in vivo. PLoS Pathog 11:e1004581
Cesarman, Ethel (2014) How do viruses trick B cells into becoming lymphomas? Curr Opin Hematol 21:358-68
Nayar, Utthara; Lu, Pin; Goldstein, Rebecca L et al. (2013) Targeting the Hsp90-associated viral oncoproteome in gammaherpesvirus-associated malignancies. Blood 122:2837-47

Showing the most recent 10 out of 18 publications