Abstract
Human T-cell leukemia virus type 1 (HTLV-1) establishes persistent infection in vivo in two distinct ways: de novo infection and clonal proliferation of infected cells. Two viral genes, Tax and HTLV-1 bZIP factor (HBZ) play critical roles in viral transcription and promotion of T-cell proliferation, respectively. Tax is a potent transactivator not only for viral transcription but also for many cellular oncogenic pathways, such as the NF-κB pathway. HBZ is a suppressor of viral transcription and has the potential to change the immunophenotype of infected cells, conferring an effector regulatory T cell (eTreg)-like signature (CD4+ CD25+ CCR4+ TIGIT+ Foxp3+) and enhancing the proliferation of this subset. Reports that mice transgenic for either gene develop malignant tumors suggest that both Tax and HBZ are involved in leukemogenesis by HTLV-1. However, the immunogenicity of Tax is very high, and its expression is generally suppressed in vivo. Recently, it was found that Tax can be expressed transiently in a small subpopulation of adult T-cell leukemia-lymphoma (ATL) cells and plays a critical role in maintenance of the overall population. HBZ is expressed in almost all infected cells except for the rare Tax-expressing cells, and activates the pathways associated with cell proliferation. These findings indicate that HTLV-1 fine-tunes the expression of viral genes to control the mode of viral propagation. The interplay between Tax and HBZ is the basis of a sophisticated strategy to evade host immune surveillance and increase transmission – and can lead to ATL as a byproduct.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) belongs to the delta type retroviruses, which include bovine leukemia virus (BLV), human T-cell leukemia virus type 2 (HTLV-2) and the simian T-cell leukemia viruses (STLVs) (Hajj et al, 2012)
HTLV-1 is a causative agent of several human diseases, including adult T-cell leukemia-lymphoma (ATL), HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis (TSP), and HTLV-1 uveitis (Matsuoka and Jeang, 2007)
Tax and HTLV-1 bZIP factor (HBZ), which are encoded in the sense and antisense transcripts, respectively, have been shown to have oncogenic properties in transgenic mouse models (Yasunaga and Matsuoka, 2011)
Summary
Human T-cell leukemia virus type 1 (HTLV-1) belongs to the delta type retroviruses, which include bovine leukemia virus (BLV), human T-cell leukemia virus type 2 (HTLV-2) and the simian T-cell leukemia viruses (STLVs) (Hajj et al, 2012). It is thought that the prolonged survival and accelerated proliferation of HTLV-1-infected cells caused by viral factors induces cellular transformation, leading to the onset of ATL after a long latent period. Transcription of HBZ is consistently detected in all ATL cases (Satou et al, 2006), suggesting that it is critical for the oncogenic mechanism of HTLV-1.
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