Abstract
Human T cell lymphotropic virus type 1 (HTLV-1) infection can lead to development of adult T cell leukemia/lymphoma (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a subset of infected subjects. Understanding the interaction between host and HTLV-1 and the molecular mechanisms associated with disease pathogenesis is critical for development efficient therapies. Two HTLV-1 genes, tax and HTLV-1 basic leucine zipper factor (HBZ), have been demonstrated to play important roles in HTLV-1 infectivity and the growth and survival of leukemic cells. Increased HTLV-1 Tax expression induces the expression of various cellular genes such as IL-2 and IL-15, which directly contributes to lymphocyte activation and immunopathogenesis in HAM/TSP patients. However, little is known about the molecular and cellular mechanism of HBZ in development of HAM/TSP. It has been reported that HBZ mRNA expression was detected in HAM/TSP patients higher than in asymptomatic carriers and correlated with proviral load and disease severity. Unlike HTLV-1 tax, HBZ escapes efficient anti-viral immune responses and therefore these reactivities are difficult to detect. Thus, it is important to focus on understanding the function and the role of HTLV-1 tax and HBZ in disease development of HAM/TSP and discuss the potential use of these HTLV-1 viral gene products as biomarkers and therapeutic targets for HAM/TSP.
Highlights
Human T lymphotropic virus type 1 (HTLV-1) is the first human retrovirus discovered belonging to the deltaretrovirus family and is thought to infect approximately 10–20 million people worldwide (Poiesz et al, 1980; de The and Bomford, 1993)
The expression of Tax in primary human astrocytomas and oligodendrogliomas resulted in robust induction of IL-1α, IL-1β, TNF-α, TNF-β, and IL-6 expression (Banerjee et al, 2007). These results suggested that increased inflammatory responses may cause disruption of blood–brain barrier (BBB) and the alteration of the BBB integrity may allow T cells to transmigrate into the central nervous system (CNS), resulting in neuroinflammation of HTLV-1-infected subjects
When Tax and HTLV-1 basic leucine zipper factor (HBZ) expression was examined in CD4+ T cells expressing CD25 and CD39 of HTLV-1-associated myelopathy/tropic spastic paraparesis (HAM/TSP) patients, HBZ mRNA expression was significantly correlated with CD39+CD4+ T cells while Tax expression was restricted to CD25-expressing CD4+ T cells regardless of CD39 expression (Leal et al, 2013)
Summary
Human T lymphotropic virus type 1 (HTLV-1) is the first human retrovirus discovered belonging to the deltaretrovirus family and is thought to infect approximately 10–20 million people worldwide (Poiesz et al, 1980; de The and Bomford, 1993). The majority of spontaneous Tax expressing cells corresponded to the large number of low abundance clones, rather than a small number of high abundance clones (Melamed et al, 2013), suggesting that clonal expansion of infected cells might be controlled by host immune response to Tax or by other viral factor such as HBZ in HAM/TSP patients. These reports demonstrated that cells with HTLV-1 provirus integrated near transcriptionally active areas could establish and expand more frequently in HAM/TSP patients, which would influence expression of HTLV-1 gene products and further contribute to the development and pathogenesis of HAM/TSP.
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