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Title: The molecular and phenotypic signature of human T-cell lymphotropic virus type 1 infected clones and their malignant potential
Author: Kagdi, Huseini Hatimbhai
ISNI:       0000 0004 7969 8527
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Aggressive Adult T cell leukemia/lymphoma (ATL), a human T lymphotropic virus type 1 (HTLV-1) -associated disease, has a poor prognosis. There is an urgent need for effective prevention and treatment. Aggressive ATL develops in patients with non-malignant HTLV-1 (asymptomatic carriers (AC) and patients with HTLV-1 associated myelopathy (HAM)) over decades with evolution from high proviral load (PVL) and non-dominant clonal growth through emergence of dominant clones and indolent to aggressive ATL. The aim of these studies was to characterize the phenotypic and molecular signature of cells contributing to in vivo HTLV-1 infected clones in these clinical states. A retrospective study of peripheral blood samples from ten HTLV-1-uninfected subjects (UI), 54 patients with non-malignant HTLV-1 infection and 22 with ATL was performed. Clonality analysis was performed by LMPCR-HTS and TCR sequencing, phenotype analysis (immunophenotype and cytokine production) by flow cytometry (protein expression) and whole transcriptome analysis (mRNA expression). The cells of the dominant clone in all patients with ATL had CD4+CCR4+CD26-CD7- immunophenotype (putative ATL cells) and produce little or no cytokines. ATL cells had a CCR7+CD127-Ki67hi immunophenotype in aggressive disease and were CCR7-CD127+Ki67lo in indolent disease. Non-dominant infected clones containing cells with an ATL immunophenotype ('ATL-like' cells) were present in patients with non-malignant HTLV-1 infection as well as in ATL. 'ATL-like' cells were CCR7-CD127+Ki67lo and cytokine producing with higher anti- and lower pro-inflammatory cytokines compared to non 'ATL-like' cells (predominantly un-infected cells). 'ATL-like' cells are mainly responsible for the differential plasma cytokine profile seen in patients with non-malignant HTLV-1 infection as well as in ATL. In conclusion, non-malignant HTLV-1 infection with high PVL leads to increased frequency of non-dominant clones containing cytokine producing 'ATL-like' cells. Indolent ATL leads to the emergence of a dominant clone with selective growth of non-cytokine producing ATL cells whilst transformation to aggressive ATL leads to ATL cells acquiring a higher proliferative and infiltrative phenotype.
Supervisor: Taylor, Graham Phillip Sponsor: Bloodwise
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral