Viruses are considered the second most important cause of malignant disease in humans, contributing up to 14-20% of all cancers worldwide. Human cancers associated with virus infection include adult T-cell leukemia (ATLL- human T-cell lymphotropic virus infection;HTLV-1 infection), non-Hodgkins lymphoma (Epstein-Barr Virus;EBV infection) and kaposi's sarcoma (human herpes virus 8;HHV8 infection). A leading cause of death in HIV-infected individuals is also caused by malignant disease induced by selected viral infection. The University of Miami (UM) School of Medicine is in a unique position to study these increasingly prevalent malignant disorders. Essentially, Southern Florida is an endemic area for viral-associated cancers and has the largest cohorts of patients with such diseases in the world. Given this situation, we have assembled a team of investigators at the University of Miami School of Medicine, Sylvester Comprehensive Cancer Center (SCCC), UM, experts in their respective fields of viral oncology and the regulation of host defense. These are Glen N. Barber, Ph.D., William Harrington Jr., M.D., Enrique Mesri, Ph.D., and Ed Harhaj, Ph.D. All are members of the Viral Oncology Program, SCCC, co-headed by Professors Harrington and Barber. Our proposal focuses on overlapping strengths prevalent within our group and takes advantage of our expertise in analyzing host defense and the importance of the interferon (IFN) pathway in naturally combating viral and malignant disease. For example, we have recently elucidated a toll-independent arm of innate immune signaling, essential for the induction of IFN and subsequent expression of anti-viral and anti-tumor genes. These important signaling pathways now appear, unsurprisingly, to be targeted by a growing number of viruses, consequences that may explain mechanisms of viral resistance to IFN therapy, latency and speculatively tumorigenesis. Our proposal focuses on further studying innate immune signaling mechanisms critical for effective host defense. Our study also encompasses the regulation of these processes by the oncoviruses HTLV-1, HHV8 and EBV. More specifically, our proposal comprises three major components: PROJECT I, Glen N. Barber, Ph.D.: Mechanisms of host defense and regulation by oncoviral encoded gene products. PROJECT II, William Harrington, Jr., M.D.: Host Defense regulation by HTLV-1. PROJECT III, Enrique Mesri, Ph.D.: HHV8 (KSHV)-Mediated Regulation of Host Defense.

Public Health Relevance

Viruses are associated with up to 15% of all cancers, and South Florida is endemic in such diseases. The objectives with this grant are to understand how viruses contribute towards cancer and to develop new therapeutics to treat such diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA128115-04
Application #
8322084
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2009-08-14
Project End
2014-07-31
Budget Start
2012-09-14
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$1,103,015
Indirect Cost
$365,590
Name
University of Miami School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Bayraktar, Ulas Darda; Diaz, Luis A; Ashlock, Brittany et al. (2014) Zidovudine-based lytic-inducing chemotherapy for Epstein-Barr virus-related lymphomas. Leuk Lymphoma 55:786-94
Charoenthongtrakul, Soratree; Gao, Linlin; Parvatiyar, Kislay et al. (2013) RING finger protein 11 targets TBK1/IKKi kinases to inhibit antiviral signaling. PLoS One 8:e53717
Gao, Linlin; Harhaj, Edward William (2013) HSP90 protects the human T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein from proteasomal degradation to support NF-*B activation and HTLV-1 replication. J Virol 87:13640-54
Lavorgna, Alfonso; Harhaj, Edward W (2013) Is there a role for ubiquitin or SUMO in human T-cell leukemia virus type 2 Tax-induced NF-*B activation? Future Virol 8:223-227
Shembade, Noula; Harhaj, Edward W (2012) Regulation of NF-?B signaling by the A20 deubiquitinase. Cell Mol Immunol 9:123-30
Harhaj, Edward W; Dixit, Vishva M (2012) Regulation of NF-*B by deubiquitinases. Immunol Rev 246:107-24
Lavorgna, Alfonso; Harhaj, Edward W (2012) EBV LMP1: New and shared pathways to NF-ýýB activation. Proc Natl Acad Sci U S A 109:2188-9
Ramos, Juan Carlos; Lossos, Izidore S (2011) Newly emerging therapies targeting viral-related lymphomas. Curr Oncol Rep 13:416-26
Charoenthongtrakul, Soratree; Zhou, Qinjie; Shembade, Noula et al. (2011) Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF-kappaB-dependent induction of SOCS1. J Virol 85:6955-62
Harhaj, Edward W; Dixit, Vishva M (2011) Deubiquitinases in the regulation of NF-?B signaling. Cell Res 21:22-39

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