Abstract
Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.
Highlights
Few studies with the closely related simian T-cell leukemia virus type 1 (STLV-1) suggested that hematopoietic cells in the bone marrow are infected. This could be confirmed by highthroughput sequencing of Human T-cell leukemia virus type 1 (HTLV-1)-infected humans, which identified identical integration sites in neutrophils, monocytes, B-cells, CD8+ T-cells, and CD4+ T-cells, which indicated that HTLV-1 infects hematopoietic stem cells (HSCs) in vivo
Thereto, Tax competes with histone deacetylase (HDAC) to bind to the HTLV-1 promoter to activate transcription and to relieve the transcriptional repression mediated by HDACs
This review will focus on histone deacetylase inhibitors (HDACi), which have been explored in the context of HTLV-1 infection or latency reversal or which seem to be promising candidates to the end of a Kill and Kill approach targeting HTLV-1 infected cells (Table 1)
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is a highly oncogenic retrovirus causing adult T-cell leukemia/lymphoma (ATLL) or inflammatory diseases like HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in up to 10% of infected individuals [1,2,3,4,5]. There is only scarce data available on HAID prevalence [9,13] The onset of these diseases is marked by a prolonged clinical and viral latency. One of the newer treatment options is Mogamulizumab, a humanized defucosylated monoclonal antibody targeting C–C chemokine receptor 4 It has been explored for the treatment of ATLL and HAM/TSP in clinical trials and is approved for the treatment of patients with relapsed or refractory CCR4+ ATLL in Japan [19,20]. Acetylation of histones at the viral promoter results in nucleosomal remodeling and a more permissive chromatin state, overall favoring transcriptional activation [7,24,26,27,28] Another determinant of transcription is the RNA polymerase II (RNA Pol II). Tax affects the initiation of viral transcription and recruits host cell factors like P-TEFb to the viral promoter to simulate transcription elongation [29,30]
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