HTLV-1 bZIP factor: the key viral gene for pathogenesis

Abstract

Human T cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. The HTLV-1 bZIP factor (HBZ) gene is constantly expressed in HTLV-1 infected cells and ATL cells. HBZ protein suppresses transcription of the tax gene through blocking the LTR recruitment of not only ATF/CREB factors but also CBP/p300. HBZ promotes transcription of Foxp3, CCR4, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). Thus, HBZ is critical for the immunophenotype of infected cells and ATL cells. HBZ also functions in its RNA form. HBZ RNA suppresses apoptosis and promotes proliferation of T cells. Since HBZ RNA is not recognized by cytotoxic T cells, HTLV-1 has a clever strategy for avoiding immune detection. HBZ plays central roles in maintaining infected T cells in vivo and determining their immunophenotype.

Keywords: HBZ; HTLV-1; Regulatory T cell; Viral oncogenesis.

Fig. 1

Effect of HBZ on bZIP factor activities. (1) Tax interacts with CREB to bind to vCREs and then recruits CBP (or p300) to activate viral transcription from the 5′ LTR. (2) HBZ inhibits Tax-dependent viral transcription by interacting with CREB and CBP/p300. (3) HBZ also stimulates its own expression by forming HBZ/JunD heterodimers capable of interacting with Sp1 bound to the 3′ LTR. (4) HBZ can also bind to ATF-3/p53 complexes, reducing ATF3′s ability to enhance p53 activity. (5 and 6) HBZ inhibits the MafB, C/EBPα, c-Jun, and JunB transcriptional activities by promoting their degradation via a proteasome-dependent pathway (5) or by sequestration into nuclear bodies (6). HBZ stimulates JunD activity (7) by inducing expression of ΔJunD, a JunD isoform that is unable to interact with the inhibitor menin. HBZ is also able to activate HMOX1 transcription by forming heterodimers with the small Mafs [42]

Fig. 2

Functions of HBZ. HBZ induces transcription of Foxp3, CCR4 and TIGIT genes. HBZ expression promotes the proliferation of T cells and inhibits their apoptosis. In addition, HBZ changes expressing T cells to an effector/memory phenotype, which is important for their migration into breast milk and semen