Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis

Retrovirology Ma et al. Retrovirology (2016) 13:16 DOI 10.1186/s12977-016-0249-x Open Access REVIEW Multifaceted functions and roles of HBZ in HTLV‑1 pathogenesis Guangyong Ma, Jun‑ichirou Yasunaga and Masao Matsuoka* Abstract Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus responsible for the development of adult T-cell leukemia (ATL). Although HTLV-1 harbors an oncogene, tax, that transforms T cells in vitro and induces leukemia in transgenic mice, tax expression is frequently disrupted in ATL, making the oncogenesis of ATL a bit mysterious. The HTLV-1 bZIP factor (HBZ) gene was discovered in 2002 and has been found to promote T-cell proliferation and cause lymphoma in transgenic mice. Thus HBZ has become a novel hotspot of HTLV-1 research. This review summarizes the current findings on HBZ with a special focus on its potential links to the oncogenesis of ATL. We propose viewing HBZ as a critical contributing factor in ATL development. Keywords: HTLV-1, HBZ, Tax, Viral oncogenesis, Regulatory T cell Background Human T-cell leukemia virus type 1 (HTLV-1) is the first human retrovirus to have been identified (in the early 1980s), and it was later demonstrated to be the causative agent of adult T-cell leukemia (ATL), an aggressive cancer of peripheral CD4 T cells [1, 2]. HTLV-1 is able to infect various cell types in vitro, yet the HTLV-1 provirus is predominantly detected in CD4 T cells in vivo [3]. The CD4 T cell tropism of HTLV-1 is likely due to selected expansion of infected CD4 T cells rather than a receptor preference, because the HTLV-1 receptor, glucose transporter 1 (GLUT1) is ubiquitously expressed [4, 5]. The HTLV-1 provirus is 9 kb long and has multiple coding regions flanked by two identical 750-bp long terminal repeats (LTRs) in the 5′ and 3′ ends (Fig. 1), both of which are composed of unique 3′ (U3), repeat (R) and unique 5′ (U5) regions. The 5′ LTR serves as the promoter for all structural genes and most accessary and regulatory genes, including the gene for the transactivator Tax, which upregulates 5′ LTR activity by recruiting cAMP response element-binding protein (CREB) to three viral CREB-responsive element (vCRE) tandem repeats in *Correspondence: ‑u.ac.jp Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan the 5′ LTR [6]. Transcriptional coactivators such as CBP/ p300 and P/CAF are also recruited to vCRE by Tax [6]. The 3′ LTR is able to initiate transcription from the negative strand of the provirus and serves as the promoter for the only antisense transcript of the virus, HTLV-1 basic leucine zipper factor (HBZ) [7–9]. Although most HTLV-1 infected individuals remain lifelong asymptomatic carriers, approximately 5 % of them will develop ATL after a long latency of decades [10]. HTLV-1 also causes several inflammatory diseases such as uveitis, dermatitis and a neurodegenerative disorder called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [11]. Review The HBZ gene Tax is of crucial importance for its unique ability to drive HTLV-1 replication and to immortalize T cells [12] and thus has long been thought to be the main causal factor of ATL. However, it has been reported that Tax expression is frequently inactivated in ATL cases by either abortive mutations in the tax gene or DNA methylation of the 5′ LTR [13–16]. In addition, a defective provirus with the 5′ LTR partially or completely deleted has been found in up to 40 % of ATL cases [17, 18]. Host immunosurveillance by cytotoxic T lymphocytes (CTLs) is thought to © 2016 Ma et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/ zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ma et al. Retrovirology (2016) 13:16 Page 2 of 9 HTLV-1 provirus 5’LTR host genome Gag-Pro-Pol 3’LTR host genome Gag Pro Pol Env p12 p30 p13 Rex (p21) Rex (p27) Tax sHBZ usHBZ Fig. 1 HTLV-1 provirus, mRNAs and proteins. HTLV-1 provirus is shown on top in blue with both LTRs painted in brown. Below, the transcripts and proteins encoded by a complete HTLV-1 provirus are shown. Sense transcripts are portrayed as black arrows with arrowheads pointing to the right, while antisense transcripts run in the opposite direction. Spliced exons are shown in solid black lines while introns are shown as dotted lines. Proteins derived from respective mRNAs are shown as empty squares be responsible for the loss of Tax expression, since Tax protein is a major target of CTLs [19]. In contrast to the 5′ LTR, the 3′ LTR remains intact and non-methylated— and the HBZ gene harbors no abortive mutations and is consistently expressed in ATL patients and HTLV-1 infected individuals [18, 20, 21]. Furthermore, HBZ mRNA abundance positively correlates with HTLV-1 proviral load in asymptomatic carriers (AC), HAM/TSP and ATL patients [22–24]. The distinct expression patterns of HBZ and tax suggest that they have different roles in the course of HTLV-1 pathogenesis. The HBZ gene has two transcription isoforms: an unspliced (usHBZ) form and a spliced (sHBZ) form. usHBZ was discovered in 2002 [8] and early publications on HBZ were exclusively based on usHBZ. The alternative transcript, sHBZ, was first reported in 2006 [25–27]. These two transcripts have different 5′ untranslated regions (UTRs) and differ slightly in the 5′ region of their coding sequences (CDS) (Fig. 1). Consequently, the usHBZ and sHBZ proteins have almost identical sequences except for the first several amino acids (MAAS for sHBZ and MVNFVSA for usHBZ). Previous studies have shown that usHBZ and sHBZ exhibit similar functions. However, since sHBZ is more abundantly expressed in infected cells [9, 22], current studies are mostly focused on sHBZ. This review mainly addresses the functions of sHBZ. The transcription of sHBZ initiates from the U5 and R regions of the 3′ LTR [25, 27], and the whole 3′ LTR likely serves as a TATA-less promoter of sHBZ [9]. sHBZ transcription terminates at a classical polyadenylation signal downstream [27]. Three vCRE [28] and three specificity protein 1 (Sp1) binding sites [9] have been discovered in the 3′ LTR, and they seem to be critical for its promoter activity. Due to the presence of vCRE, the activity of the 3′ LTR is enhanced by Tax via a CREB-dependent mechanism [28]. HBZ, by recruiting JunD to the Sp1 sites, also enhances the activity of the 3′ LTR [29]. It is interesting that the activity of the 3′ LTR seems to respond to some stimuli in an opposite way from that of the 5′ (...truncated)