IRUS Total

The Host Immune Response to HTLV-1 Infection

File Description SizeFormat 
Tattermusch-S-2012-PhD-Thesis.pdf6.45 MBAdobe PDFView/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:Medicine PhD theses

Unless otherwise indicated, items in Spiral are protected by copyright and are licensed under a Creative Commons Attribution NonCommercial NoDerivatives License.

Creative Commons