Immunopathogenesis of Human T-Cell Leukemia Virus Type-1-Associated Myelopathy/Tropical Spastic Paraparesis: Recent Perspectives

Mineki Saito,Charles R M Bangham

doi:10.1155/2012/259045

Abstract

Human T-cell leukemia virus type-1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic progressive myelopathy characterized by spastic paraparesis, sphincter dysfunction, and mild sensory disturbance in the lower extremities. Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence from host population genetics, viral genetics, DNA expression microarrays, and assays of lymphocyte function suggests that complex virus-host interactions and the host immune response play an important role in the pathogenesis of HAM/TSP. Especially, the efficiency of an individual's cytotoxic T-cell (CTL) response to HTLV-1 limits the HTLV-1 proviral load and the risk of HAM/TSP. This paper focuses on the recent advances in HAM/TSP research with the aim to identify the precise mechanisms of disease, in order to develop effective treatment and prevention.

Highlights

Human T-cell leukemia virus type-1 (HTLV-1) is a human retrovirus etiologically associated with adult T-cell leukemia (ATL) [1,2,3] and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [4, 5]
Recent data suggest that the frequency of invariant NKT cells in the peripheral blood of HAM/TSP patients is significantly decreased when compared with healthy subjects and/or asymptomatic carriers (ACs) [53, 54]. These findings indicate that the activity of the Natural Killer (NK) or NKT cell response was associated with the absence of HAM/TSP
A less efficient Cytotoxic T-Lymphocyte (CTL) response against HTLV-1 may cause a higher proviral load (PVL) and higher antigen expression in infected individuals, which in turn lead to activation and expansion of antigen-specific T-cell responses, subsequent induction of large amounts of proinflammatory cytokines and chemokines, and progression to HAM/TSP

Summary

Introduction

Human T-cell leukemia virus type-1 (HTLV-1) is a human retrovirus etiologically associated with adult T-cell leukemia (ATL) [1,2,3] and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [4, 5]. Cells ex vivo [42], granzymes and perforin are more highly expressed in individuals with a low PVL [43], and the lytic efficiency of the CD8+ T cell response, that is, the fraction of autologous HTLV-1-expressing cells eliminated per CD8+ T cell per day, was inversely correlated with both PVL and the rate of spontaneous proviral expression [44] These findings indicate that the CTL against HTLV-1 reduces PVL and risk of HAM/TSP. These results indicate that the higher PVL observed in patients with HAM/TSP was attributable to a larger number of UISs but not, as previously thought, from a difference in clonality They obtained evidence that the abundance of established HTLV1 clones is determined by genomic features of the host DNA flanking the provirus. Negative selection of infected clones, probably by CTLs during chronic infection, favors establishment of proviruses integrated in transcriptionally silenced DNA, and this selection is more efficient in ACs than in HAM/TSP, indicating the selection of HTLV-1-infected T-cell clones with low pathogenic potential

Innate Immune Response

Findings

Concluding Remarks