Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is etiologically associated with several AIDS-related malignancies including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). In AIDS patients, oral KS is a common manifestation and often the first pathological symptom to appear, but KS frequently evolves into fatal stages involving visceral organs. Despite the success of HAART in some developed countries, KS remains an important disease of morbidity and mortality in US and worldwide. Understanding the mechanism of KSHV-induced pathogenesis could provide a scientific basis for developing novel preventive and therapeutic targets for KSHV-related malignancies. Current evidences indicate that KSHV lytic replication and the resulting constant new infection are important for sustaining the growth of KS tumors. Thus, it is essential to understand the molecular mechanisms and signaling pathways that regulate KSHV infection and replication. Our preliminary studies have shown that KSHV activates MEK, JNK and p38 multiple mitogen-activated protein kinase (MAPK) pathways during primary infection. Importantly, inhibitors of all three MAPK pathways reduce KSHV infectivity and the production of infectious virions during productive primary infection of primary human umbilical vein endothelial cells (HUVEC), and KSHV reactivation in latently-infected PEL cells. Based on these results, we hypothesize that multiple MAPK pathways regulate KSHV infection and replication during productive primary infection and reactivation from latency. To test this hypothesis, we will define the molecular mechanisms by which multiple MAPK pathways regulate KSHV infectivity (Aim I), KSHV lytic replication during productive primary infection (Aim II), and KSHV reactivation from latency (Aim III). The proposed study is highly significant because it will not only help understand the cellular pathways and mechanisms controlling KSHV infection and replication but also identify potential novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124332-04
Application #
7758374
Study Section
Special Emphasis Panel (ZRG1-AARR-C (04))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2007-04-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$277,400
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Tan, Brandon; Liu, Hui; Zhang, Songyao et al. (2018) Viral and cellular N6-methyladenosine and N6,2'-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. Nat Microbiol 3:108-120
Gruffaz, Marion; Zhou, Shenghua; Vasan, Karthik et al. (2018) Repurposing Cytarabine for Treating Primary Effusion Lymphoma by Targeting Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Replications. MBio 9:
Cheng, Fan; Ramos da Silva, Suzane; Huang, I-Chueh et al. (2018) Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22. J Virol 92:
Jeon, Hyungtaek; Yoo, Seung-Min; Choi, Hyo Sun et al. (2017) Extracellular vesicles from KSHV-infected endothelial cells activate the complement system. Oncotarget 8:99841-99860
He, Meilan; Tan, Brandon; Vasan, Karthik et al. (2017) SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells. J Pathol 242:309-321
Yuan, Hongfeng; Tan, Brandon; Gao, Shou-Jiang (2017) Tenovin-6 impairs autophagy by inhibiting autophagic flux. Cell Death Dis 8:e2608
Li, W; Hu, M; Wang, C et al. (2017) A viral microRNA downregulates metastasis suppressor CD82 and induces cell invasion and angiogenesis by activating the c-Met signaling. Oncogene 36:5407-5420
Yuan, Hongfeng; He, Meilan; Cheng, Fan et al. (2017) Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy. Oncotarget 8:14912-14924
Gruffaz, Marion; Vasan, Karthik; Tan, Brandon et al. (2017) TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway. Cancer Res 77:7094-7108
Zhu, Ying; Li, Tingting; Ramos da Silva, Suzane et al. (2017) A Critical Role of Glutamine and Asparagine ?-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus. MBio 8:

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