Poster abstracts

Poster number 97 submitted by Jacob Al-Saleem

The Role of Tax-1 and The Alternative NF-κB Signaling Pathway in HTLV Transformation

Jacob Al-Saleem (Department of Veterinary Biosciences, The Ohio State University), Patrick L. Green (Department of Veterinary Biosciences, The Ohio State University)

Abstract:
Human T-cell Leukemia Virus Type-1 (HTLV-1) is a complex retrovirus infecting 15-25 million people worldwide. HTLV-1 is the etiological agent of an aggressive malignancy of CD4+ T cells termed Adult T-Cell Leukemia (ATL). ATL patients, on average, survive one year from disease onset. The HTLV-1 regulatory protein Tax is required for HTLV-1-mediated cellular transformation both in vitro and in vivo. Tax primarily functions to promote transcription of viral genes, but has also been shown to deregulate cellular genes leading to cell growth and genetic instability. Previous studies showed that Tax induces NF-κB by two distinct signaling/activation pathways: the classical pathway, which is rapid, and the alternative pathway, which is delayed. The exact role of the alternative pathway in HTLV-1-mediated transformation is unknown. We propose that Tax interaction with the alternative NF-κB pathway is important for HTLV-induced pathogenesis. To test this hypothesis we will identify and utilize Tax mutants that are deficient in their ability to activate the NF-κB pathways. Viruses containing these mutant forms of tax will be used to infect primary peripheral blood mononuclear cells (PBMCs) and transformation will be monitored via a cellular proliferation assay. We also plan to identify Tax-1 binding partners that are important for Tax-mediated activation of the NF-κB pathway. To identify these binding partners we generated S-protein epitope tagged Tax expression vectors for both wild type and NF-κB activation deficient tax genes. We expressed tagged Tax proteins in 293T cells and performed immunoprecipitation followed by mass spectrometry to identify binding partners. By comparing the differences between the wild type Tax and mutant Tax binding partners we will be able to identify candidate proteins required for Tax-mediated activation of the alternative NF-κB pathway. We hypothesis that these candidates could then be used in future studies as clinical targets to treat patients with ATL.

Keywords: HTLV, Tax, NF-B