Abstract
Efficient HTLV-1 viral transmission occurs through cell-to-cell contacts. The Tax viral transcriptional activator protein facilitates this process. Using a comparative transcriptomic analysis, we recently identified a series of genes up-regulated in HTLV-1 Tax expressing T-lymphocytes. We focused our attention towards genes that are important for cytoskeleton dynamic and thus may possibly modulate cell-to-cell contacts. We first demonstrate that Gem, a member of the small GTP-binding proteins within the Ras superfamily, is expressed both at the RNA and protein levels in Tax-expressing cells and in HTLV-1-infected cell lines. Using a series of ChIP assays, we show that Tax recruits CREB and CREB Binding Protein (CBP) onto a c-AMP Responsive Element (CRE) present in the gem promoter. This CRE sequence is required to drive Tax-activated gem transcription. Since Gem is involved in cytoskeleton remodeling, we investigated its role in infected cells motility. We show that Gem co-localizes with F-actin and is involved both in T-cell spontaneous cell migration as well as chemotaxis in the presence of SDF-1/CXCL12. Importantly, gem knock-down in HTLV-1-infected cells decreases cell migration and conjugate formation. Finally, we demonstrate that Gem plays an important role in cell-to-cell viral transmission.
Highlights
Five to 10 million people are infected with the HTLV-1 retrovirus (Human T-cell Leukemia Virus Type 1) worldwide [1]; and 1–6% of infected people will develop either Adult T-cell Leukemia (ATL) [2], a malignant lymphoproliferation of mature activated T-cells, or inflammatory disorders, such as Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/ HAM) [3,4].The long period of clinical latency between primo-infection and ATL outcome suggests that the pathogenesis is a complex multistep process [5]
We found that Gem was highly upregulated both at the RNA and protein levels in Taxexpressing cells and HTLV-1-infected cell lines
We demonstrated that Gem is involved in cellular migration of HTLV-1-infected cells
Summary
Five to 10 million people are infected with the HTLV-1 retrovirus (Human T-cell Leukemia Virus Type 1) worldwide [1]; and 1–6% of infected people will develop either Adult T-cell Leukemia (ATL) [2], a malignant lymphoproliferation of mature activated T-cells, or inflammatory disorders, such as Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/ HAM) [3,4].The long period of clinical latency between primo-infection and ATL outcome suggests that the pathogenesis is a complex multistep process [5]. The exact mechanism by which infected individuals develop ATL is still debated, the Tax viral oncoprotein has clearly been associated with cell transformation. Tax immortalizes/transforms T-lymphocytes in vivo and in vitro [8] and promotes tumors in transgenic mice [9]. Efficient transmission of HTLV-1 from infected to uninfected T-cells relies on cell-to-cell contacts, both in vitro and likely in vivo [7,11]. Transmission of HTLV-1 particles to an uninfected T-lymphocyte occurs through two mutually non-exclusive models: (i) formation of a virological synapse between an infected lymphocyte and an un-infected lymphocyte (involving cytoskeleton reorganization and reorientation of the microtubule-organizing center (MTOC) in the infected T-lymphocyte) [12] or (ii) formation and transfer of a viral biofilm-like structure [13].
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