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The Host Immune Response to HTLV-1 Infection
File | Description | Size | Format | |
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Tattermusch-S-2012-PhD-Thesis.pdf | 6.45 MB | Adobe PDF | View/Open |
Title: | The Host Immune Response to HTLV-1 Infection |
Authors: | Tattermusch, Sonja |
Item Type: | Thesis or dissertation |
Abstract: | Human T-lymphotropic virus Type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ~4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. In this study we aimed to identify patterns in frequencies of peripheral leukocyte populations and blood gene expression profiles of HTLV-1 carriers that suggest new hypotheses as to the mechanisms of HTLV-1 persistence and HAM/TSP pathology. Flow cytometric immunophenotyping of peripheral blood leukocytes revealed abnormal activation and maturation profiles of effector T cells but not antigen-presenting cells. High frequencies of circulating granzyme and perforin-rich CD8+ T cells were associated with an increased probability of HAM/TSP. However, the cytolytic capacity of these T cells is not known as although they accumulated cytolytic proteins, granzyme mRNA levels were down-regulated in patients with HAM/TSP. Furthermore, presence of HAM/TSP was associated with an expansion of CD56-negative NK cells, which are thought to have decreased cytolytic functions. Blood gene expression profiles identified perturbations of the p53 signalling pathway as a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. Based on our findings we hypothesise that impaired NK cell and T cell-mediated immune responses result in high HTLV-1 proviral loads but that the over-expression of a subset of IFN-stimulated genes contributes to the development of HAM/TSP. |
Issue Date: | 2012 |
Date Awarded: | Aug-2012 |
URI: | http://hdl.handle.net/10044/1/9916 |
DOI: | https://doi.org/10.25560/9916 |
Supervisor: | Bangham, Charles |
Sponsor/Funder: | Wellcome Trust (London, England) |
Department: | Medicine: Immunology |
Publisher: | Imperial College London |
Qualification Level: | Doctoral |
Qualification Name: | Doctor of Philosophy (PhD) |
Appears in Collections: | Department of Immunology and Inflammation PhD Theses |