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double-stranded DNA that integrates into the host cell genome as a provirus. The proviral dsDNA is marked at both ends by long terminal repeats (LTRs), which serve as promoters for sense (5′-LTR) and antisense (3′-LTR) tran- scription.10 Two key oncogenic proteins, Tax and HBZ (HTLV-1 basic leucine zipper factor) (Figure 1), are encod-
ed in the pX region in the 3’ end of the provirus.
An estimated 10-15 million people worldwide are infected with HTLV-1.9 The virus is transmitted vertically (breast milk) and horizontally (sexual contact, blood products), infecting primarily mature CD4+ T cells with a CD25+FOXP3+ regulatory T-cell (Treg) phenotype.11 Direct
Figure 1. Transmission, replication, and oncogenesis of HTLV-1 in adult T-cell leukemia/lymphoma (ATL). Transmission of infected CD4+CD25+FOXP3+ cells occurs via vertical and horizontal routes to a new host. Reverse transcribed HTLV-1 DNA is integrated into the DNA of host cells. and direct cell-to-cell contact and mitosis drives viral replication leading to a clonally diverse population of infected cells. Two transcription regulators, Tax and the HTLV-I basic leucine zipper factor (HBZ) are essential for oncogenesis. Tax up-regulates the P13K/AkT and NFκB pathways including through IL-15, and down-regulates p53. HBZ up-regulates TGFβ, FOXP3, and the C-C chemokine receptor 4 (CCR4) while down-regulating INFα, IL-2, and TNF. After decades of complex interactions between these molecules, together with the acquisition of new mutations, immune dysregulation, and host-specific factors, ATL develops in 2-5% of carriers. The defucosylated monoclonal antibody moga- mulizumab binds CCR4 leading to enhanced antibody-dependent cellular cytotoxicity (ADCC).
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