Our objectives here are to further understand mechanisms of innate immune signaling and clarify mechanisms by which select oncogenic viruses such as HTLV-1 and HHV8 may subvert these important signaling pathways. We believe that elucidating these processes will have significant impact on understanding pathogenesis and on the development of novel therapeutics and vaccines to combat oncoviral-related malignant disease. While the cellular signaling molecules required for recognizing virus infection remain to be fully defined, it has recently been reported that the DExD/H box RNA helicases, RIG-I (Retinoic acid inducible gene-1) and MDA5 (melanoma differentiation antigen 5) are key players in recognizing viral dsRNA species to trigger innate immune responses. Importantly, ours and others data confirm that the molecule RIP1 is also required to facilitate DExD/H box-mediated signaling. Of note is that we have observed that HTLV-1 and HHV-8 encoded Tax and vIRFI, respectively, may inhibit these important pathways, mechanisms that may explain viral pathogenicity and modes of latency. Given these data, we aim to do the following: l.)We have recently identified that a mitochondrial protein GRIM19/B16.6 associates with RIG-I and MDA5. Given this, we aim to explore the importance of GRIM19/B16.6 in innate signaling processes, including potential suppression by HHV8 vIRFI and HPV E6. II.) We have demonstrated that RIP1 is important in facilitating RIG-I/MDA5 signaling. Our data also indicates that RIP1 can bind to GRIM19 as well as HTLV-1 Tax. We therefore aim to further study the importance of RIP1 in innate signaling as well as potential repression by the oncoviral protein Tax. III.) Given that we have observed that Tax inhibits innate immune signaling, and that innate signaling is defective in HTLV-1 induced ATL.
we aim to evaluate the use of VSV as an oncolytic agent to treat such diseases. Such therapeutic approaches have been designed based on data obtained from Aims I and II. We anticipate that these studies will improve our knowledge of oncognesis and provide new concepts for the rational design of novel drugs and vaccine strategies.

Public Health Relevance

Innate immune responses are essential for mounting an effective host response against virus infection. This proposal intends to understand these processes as well as understand how viruses subvert such processes to cause disease. This project will also utilize information gained through these studies to design new therapeutics to combat viral-related cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA128115-05
Application #
8546183
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$275,273
Indirect Cost
$90,172
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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Harhaj, Edward W; Dixit, Vishva M (2011) Deubiquitinases in the regulation of NF-?B signaling. Cell Res 21:22-39

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