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.
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.
|Betancourt, Dillon; Ramos, Juan Carlos; Barber, Glen N (2015) Retargeting Oncolytic Vesicular Stomatitis Virus to Human T-Cell Lymphotropic Virus Type 1-Associated Adult T-Cell Leukemia. J Virol 89:11786-800|
|Zhou, Qinjie; Lavorgna, Alfonso; Bowman, Melissa et al. (2015) Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon. J Biol Chem 290:14729-39|
|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|
|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-ÎºB activation and HTLV-1 replication. J Virol 87:13640-54|
|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|
|Bhatt, Shruti; Ashlock, Brittany M; Toomey, Ngoc L et al. (2013) Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest 123:2616-28|
|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-ÎºB signaling by the A20 deubiquitinase. Cell Mol Immunol 9:123-30|
|Lavorgna, Alfonso; Harhaj, Edward W (2012) EBV LMP1: New and shared pathways to NF-Ã½Ã½B activation. Proc Natl Acad Sci U S A 109:2188-9|
|Harhaj, Edward W; Dixit, Vishva M (2012) Regulation of NF-ÎºB by deubiquitinases. Immunol Rev 246:107-24|
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