Infection with human T cell Leukemia virus (HTLV-1) can cause Adult T-cell Leukemia (ATL) or the neurological disorder HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Although the majority of HTLV-1--infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% will develop either ATL or HAM/TSP. The factors that determine HTLV-1 pathogenesis remain elusive, and therefore represent a serious obstacle in the establishment of effective therapies for HTLV-1-associated diseases. / Using gene expression profiling of CD4+ T-lymphocytes isolated from HTLV-1-infected individuals, we identified candidate genes differentially regulated in HTLV-1-associated diseases. Of particular interest, SOCS1 was up-regulated in HAM/TSP and AC patients -- but not in ATL. SOCS1 positively correlated with HTLV-1 mRNA in HAM/TSP patient samples. SOCS1-mediated degradation of IRF3 - inhibited antiviral signaling during HTLV-1 infection. Our study reveals a novel evasion mechanism utilized by HTLV-1 which leads to increased retroviral replication, without triggering an IRF3-dependent interferon response. Thus, targeting SOCS1 could represent a potential new approach to enhance the therapeutic potency of IFN-alpha/beta treatment in HAM/TSP disease. / Although treatment of hematological malignancies has improved considerably, this has not benefited ATL patients, as they are completely refractory to conventional chemotherapeutic regimens. Oncolytic viruses, such as Vesicular stomatitis virus (VSV), have emerged as a potential treatment for cancer. Here we show that in vitro VSV infection induced significant oncolysis in highly proliferating primary ATL cells, but not in primary Chronic Lymphocytic Leukemia (CLL) cells which are arrested in the G0 phase. As chronic activation and proliferation is characteristic of ATL cells, we examined the effect of T-cell activation on VSV permissiveness and lysis. Activation of primary CD4+ T-lymphocytes was sufficient to induce VSV replication and VSV-triggered cell death, suggesting that cellular signaling pathways - ERK, JNK or AKT - that promote VSV replication are engaged during T-cell activation. Similarly, mitogenic activation of primary CLL promotes the exit from G0 and entrance into the cell cycle, rendering them susceptible to VSV-mediated oncolysis. Moreover, a global increase in protein translation mediated by the activation of mTOR and eIF4E was crucial for VSV replication in primary lymphocytes. These findings provide novel molecular targets for ATL and CLL therapeutics.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111920 |
| Date | January 2010 |
| Creators | Oliere, Stéphanie |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | (Department of Microbiology and Immunology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 003520509, proquestno: AAINR74762, Theses scanned by UMI/ProQuest. |
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