Role of HTLV-1 Tax and HBZ in the Pathogenesis of HAM/TSP

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.

Differential expression of DLG1 as a common trait in different human diseases: an encouraging issue in molecular pathology

“…Interestingly, such cells not only present low suppressive activity but also change to a proinflammatory phenotype (Araya et al, 2014). This phenomenon was explained in part by the activity of the HTLV-1 Tax protein, a key player for HTLV-1 replication, which is expressed at high levels in HAM/TSP (Araya et al, 2011;Enose-Akahata et al, 2017). HTLV-1 Tax has been reported to downregulate foxp3 expression (a transcription factor crucial for Tregs Brought to you by | Göteborg University -University of Gothenburg Authenticated Download Date | 12/6/18 11:24 AM DLG1 expression in different human diseases 9 / 23 suppressive activities); however, it may use further mechanisms to interfere with Tregs functions.…”

The Role of Chemokines in the Pathogenesis of HTLV-1

“…HBZ also plays a crucial role in the pathogenesis of ATL and HAM/TSP (Satou et al, 2006;Enose-Akahata et al, 2017). It has been shown that HBZ interacts with cAMP response element-binding protein (CREB) transcription factor, suppresses the Tax-mediated transactivation, and inhibits the canonical NF-kB pathway (Gaudray et al, 2002;Lemasson et al, 2007;Zhao et al, 2009).…”

Transactivation of human endogenous retroviruses by tumor viruses and their functions in virus-associated malignancies

“…The viral Tax protein has been considered to play an important role in the development of HTLV-1-associated diseases. HTLV-1 Tax protein performs the powerful function of activator to modulate the expression of many viral and cellular genes, such as CREB, NF-κB, and SRF 72 , 73 .…”