Kaposi's sarcoma (KS) remains as an important cancer in AIDS patients despite anti-retroviral therapy. It is the most common cancer in both HIV-positive and -negative populations in many African countries. Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication is essential for KS development, and is an effective prognostic marker for KS. In the current funding period, we have identified ERK, p38 and JNK mitogen- activated protein kinase (MAPK) pathways as the essential mediators of KSHV lytic replication. Furthermore, we have shown that reactive oxygen species (ROS) hydrogen peroxide is essential and sufficient for activating KSHV lytic replication. Significantly, ROS scavengers such as antioxidant N-acetyl-L-cysteine (NAC) inhibit KSHV replication in vitro and in a primary effusion lymphoma (PEL) mouse model, and slows the progression of lymphoma. The objective of this application is to further dissect the molecular mechanism by which MAPK pathways and ROS mediate KSHV lytic replication induced by physiological triggers including inflammatory cytokines and hypoxia, and examine the preventive and therapeutic effect of targeting ROS for inhibiting KSHV replication and KS development. The central hypothesis is that inflammatory cytokines and hypoxia activate MAPK pathways and induce ROS, resulting in the activation of KSHV lytic replication, and as a result, ROS scavengers can effectively inhibit KSHV lytic replication and KS development. We have recently developed a novel KSHV-induced KS model, which is particularly useful for preclinical testing of novel agents targeting KSHV lytic replication and KS development. We will test the hypothesis by performing the following four Specific Aims: 1) To examine the individual and combined effects of hypoxia and inflammatory cytokines on activating KSHV lytic replication, and the involvement of ROS and MAPK pathways;2) To define the molecular interactions of ROS and MAPK pathways that mediate KSHV lytic replication induced by hypoxia and inflammation cytokines;3) To define KSHV epigenetic signatures in MAPK pathways-mediated viral lytic replication induced by ROS, inflammation cytokines and hypoxia;and 4) To examine the preventive and therapeutic effect of ROS scavengers on KSHV lytic replication and KS development in a novel KSHV-induced KS model. The proposed project is highly significant because it will define the molecular basis underlying KSHV lytic replication induced by physiological triggers, and identify novel intervention targets for KSHV- induced malignancies. It will employ innovative contemporary technologies and a novel KSHV-induced KS model. We expect to illustrate an essential role of ROS and MAPK pathways in KSHV lytic replication, and demonstrate efficient inhibition of KSHV lytic replication and KS development by ROS scavenger NAC, which should establish the basis for future clinical trials for KSHV-induced malignancies in HIV patients. Because of their wide availability and affordability, NAC and other antioxidants are attractive agents for KSHV-associated malignancies, particularly in underserved populations and in Africa.

Public Health Relevance

Kaposi's sarcoma, caused by infection of Kaposi's sarcoma-associated herpesvirus (KSHV), is a common malignancy in AIDS patients in US and worldwide, inflicting morbidity and mortality to the society. This project will investigate the mechanism of KSHV replication and Kaposi's sarcoma development, which can lead to the identification potential targets for the prevention and treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA124332-07
Application #
8541542
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2006-07-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$302,252
Indirect Cost
$117,952
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zhu, Ying; Huang, Yufei; Jung, Jae U et al. (2014) Viral miRNA targeting of bicistronic and polycistronic transcripts. Curr Opin Virol 7:66-72
Jones, Tiffany; Ramos da Silva, Suzane; Bedolla, Roble et al. (2014) Viral cyclin promotes KSHV-induced cellular transformation and tumorigenesis by overriding contact inhibition. Cell Cycle 13:845-58
Li, Qiuhua; He, Meilan; Zhou, Fuchun et al. (2014) Activation of Kaposi's sarcoma-associated herpesvirus (KSHV) by inhibitors of class III histone deacetylases: identification of sirtuin 1 as a regulator of the KSHV life cycle. J Virol 88:6355-67
Moody, Rosalie; Zhu, Ying; Huang, Yufei et al. (2014) Correction: KSHV MicroRNAs Mediate Cellular Transformation and Tumorigenesis by Redundantly Targeting Cell Growth and Survival Pathways. PLoS Pathog 10:
Lee, Myung-Shin; Jones, Tiffany; Song, Dae-Yong et al. (2014) Exploitation of the complement system by oncogenic Kaposi's sarcoma-associated herpesvirus for cell survival and persistent infection. PLoS Pathog 10:e1004412
Liang, Deguang; Hu, Hao; Li, Shasha et al. (2014) Oncogenic herpesvirus KSHV Hijacks BMP-Smad1-Id signaling to promote tumorigenesis. PLoS Pathog 10:e1004253
Bai, Zhiqiang; Huang, Yufei; Li, Wan et al. (2014) Genomewide mapping and screening of Kaposi's sarcoma-associated herpesvirus (KSHV) 3' untranslated regions identify bicistronic and polycistronic viral transcripts as frequent targets of KSHV microRNAs. J Virol 88:377-92
Zhu, Ying; Haecker, Irina; Yang, Yajie et al. (2013) ?-Herpesvirus-encoded miRNAs and their roles in viral biology and pathogenesis. Curr Opin Virol 3:266-75
Ye, Feng-Chun; Zhou, Fu-Chun; Nithianantham, Stanley et al. (2013) Kaposi's sarcoma-associated herpesvirus induces rapid release of angiopoietin-2 from endothelial cells. J Virol 87:6326-35
Ye, Fengchun; Lattif, Ali Abdul; Xie, Jianping et al. (2012) Nutlin-3 induces apoptosis, disrupts viral latency and inhibits expression of angiopoietin-2 in Kaposi sarcoma tumor cells. Cell Cycle 11:1393-9

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