Splicing-dependent restriction of the HBZ gene by Tax underlies biphasic HTLV-1 infection

• Published in: PLoS pathogens Vol. 21; no. 7; p. e1013381
• Main Authors: Liang, Yi, Lyu, Chenyang, Xu, Shuwen, Tan, Chenxin, Jiang, Qian, Liu, Benquan, Yang, Sikai, Huang, Weijia, Zhou, Ruoning, Yuan, Xiaoyi, Zuo, Xiaorui, Matsuoka, Masao, Ma, Guangyong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2025; Public Library of Science (PLoS)
• Subjects: Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Biology and life sciences; Gene Expression Regulation, Viral; Gene Products, tax - genetics; Gene Products, tax - metabolism; HTLV-I Infections - genetics; HTLV-I Infections - metabolism; HTLV-I Infections - virology; Human T-lymphotropic virus 1 - genetics; Human T-lymphotropic virus 1 - physiology; Humans; Medicine and Health Sciences; Research and analysis methods; Retroviridae Proteins - genetics; Retroviridae Proteins - metabolism; RNA Splicing; Virus Replication
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1013381

HTLV-1 is an oncovirus that encodes a transactivator Tax and a regulatory gene HBZ. HTLV-1 early or infectious replication depends on Tax; during HTLV-1 late infection, HBZ plays a crucial role in driving the proliferation of infected cells and maintaining viral persistence. The biphasic replication pattern of HTLV-1 dictated by Tax and HBZ represents a result of viral host adaptation, but how HTLV-1 coordinates Tax and HBZ expression to facilitate early and late infection remains elusive. Here we reveal that HBZ RNA splicing exhibits distinct patterns in Tax+ and Tax- HTLV-1 infected cells. We demonstrate that Tax interacts with the host spliceosome and inhibits HBZ splicing by competitively binding splicing factors including WDR83 and GPATCH1. As a result, Tax confers a natural constraint on HBZ, counterbalancing its anti-replication effect at HTLV-1 early infection, while unleashing HBZ to drive HTLV-1 mitotic propagation during late infection. The splicing-dependent restriction of HBZ by Tax thus represents a critical interplay central to HTLV-1 persistence.