Abstract
BackgroundHuman T-lymphotropic virus type-1 (HTLV-1) is a deltaretrovirus that causes adult T-cell leukemia/lymphoma and is implicated in a variety of lymphocyte-mediated disorders. HTLV-1 contains both regulatory and accessory genes in four pX open reading frames. pX ORF-II encodes two proteins, p13II and p30II, which are incompletely defined in the virus life cycle or HTLV-1 pathogenesis. Proviral clones of the virus with pX ORF-II mutations diminish the ability of the virus to maintain viral loads in vivo. Exogenous expression of p30II differentially modulates CREB and Tax-responsive element-mediated transcription through its interaction with CREB-binding protein/p300 and represses tax/rex RNA nuclear export.ResultsHerein, we further characterized the role of p30II in regulation of cellular gene expression, using stable p30II expression system employing lentiviral vectors to test cellular gene expression with Affymetrix U133A arrays, representing ~33,000 human genes. Reporter assays in Jurkat T cells and RT-PCR in Jurkat and primary CD4+ T-lymphocytes were used to confirm selected gene expression patterns. Our data reveals alterations of interrelated pathways of cell proliferation, T-cell signaling, apoptosis and cell cycle in p30II expressing Jurkat T cells. In all categories, p30II appeared to be an overall repressor of cellular gene expression, while selectively increasing the expression of certain key regulatory genes.ConclusionsWe are the first to demonstrate that p30II, while repressing the expression of many genes, selectively activates key gene pathways involved in T-cell signaling/activation. Collectively, our data suggests that this complex retrovirus, associated with lymphoproliferative diseases, relies upon accessory gene products to modify cellular environment to promote clonal expansion of the virus genome and thus maintain proviral loads in vivo.
Highlights
Human T-lymphotropic virus type-1 (HTLV-1) is a deltaretrovirus that causes adult T-cell leukemia/lymphoma and is implicated in a variety of lymphocyte-mediated disorders
Tax is a nuclear and cytoplasmic localizing phosphoprotein that interacts with cellular transcription factors and activates transcription from the viral promoter, Taxresponsive element (TRE) and enhancer elements of various cellular genes associated with host cell proliferation [6]
There are four proteins expressed from these open reading frames (ORF) – p12I, p27I, p13II, and p30II. pX ORFs I and II mRNAs are present in infected cell lines and freshly isolated cells from HTLV-1-infected subjects [9], as well as in adult T cell leukemia/lymphoma (ATL) and HAM/ TSP patients [10]
Summary
Human T-lymphotropic virus type-1 (HTLV-1) is a deltaretrovirus that causes adult T-cell leukemia/lymphoma and is implicated in a variety of lymphocyte-mediated disorders. Human T-lymphotropic virus type 1 (HTLV-1), the first characterized human retrovirus, causes adult T cell leukemia/lymphoma (ATL) and is associated with several lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1]. The mechanism by which the virus causes oncogenic transformation of host T lymphocytes is incompletely understood, altered gene expression has been associated with the initiation or progression of ATL [3]. This complex retrovirus encodes structural and enzymatic gene products, as well as regulatory and accessory proteins from open reading frames (ORF) in the pX region between env and the 3' long terminal repeat (LTR) of the provirus [4]. Antibodies [11,12] and cytotoxic T cells [13] that recognize recombinant proteins or peptides of the pX ORF I and II proteins are present in HTLV-1 infected patients and asymptomatic carriers
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