Hussein Osama, Mahgoub Mohamed, Shichijo Takafumi, Nakagawa So, Tanabe Junko, Akari Hirofumi, Miura Tomoyuki, Matsuoka Masao, Yasunaga Jun-Ichirou
Department of Hematology, Rheumatology, and Infectious Diseases, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
PLoS Pathog. 2025 May 9;21(5):e1013158. doi: 10.1371/journal.ppat.1013158. eCollection 2025 May.
Human T-cell leukemia virus type 1 (HTLV-1) is derived from simian T-cell leukemia virus type 1 (STLV-1), and together they form a broader category known as primate T-cell leukemia virus type 1 (PTLV-1). PTLV-1 encodes multiple proteins from overlapping open reading frames (ORFs) in the pX region. This study aims to characterize the conservation of these proteins in different PTLV-1 subtypes and their role in pathogenesis. For the first time, we report the full-length proviral sequence of an STLV-1 strain isolated from chimpanzee and African green monkey. Phylogenetic analysis reveals high conservation of the accessory proteins p12, p30, and p13 in the HTLV-1a subtype. Conversely, some African PTLV-1 subtypes exhibit loss of ORFs for p12 or p13. For Asian subtypes, simian strains often lack p12, p13, or p30 proteins, whereas human strains retain the ORFs of p30 and p13 but not p12. To assess the infectivity of a simian strain of PTLV-1 lacking ORFs for p12, p13, and p30, we constructed a molecular clone from a naturally infected Japanese macaque (Mfu: Macaca fuscata) and compared it with HTLV-1a. Using a reporter assay and ELISA, we found similar infectivity to Jurkat T cells; however, STLV-1 Mfu exhibited impaired infectivity in the monocytic cell line THP-1. Additionally, despite the conservation of the HTLV-1/STLV-1 bZIP factor (HBZ/SBZ) ORFs, HBZ/SBZ proteins derived from HTLV-1a and African PTLV-1 subtypes induce significantly higher activation of the TGF-β/Smad signaling pathway than those from Asian subtypes. Collectively, our findings suggest that the acquisition of the accessory proteins by PTLV-1 subtypes potentially confers an advantageous adaptation of PTLV-1 during infection in apes, including humans. Moreover, among PTLV-1 strains, HBZ/SBZ had varying degrees of activity on the TGF-β/Smad pathway; this fact underscores the complex interplay between viral proteins and host signaling pathways, possibly influencing the viral pathogenicity in different species.
人类T细胞白血病病毒1型（HTLV-1）源自猴T细胞白血病病毒1型（STLV-1），它们共同构成了一个更广泛的类别，即灵长类T细胞白血病病毒1型（PTLV-1）。PTLV-1在pX区域通过重叠开放阅读框（ORF）编码多种蛋白质。本研究旨在表征这些蛋白质在不同PTLV-1亚型中的保守性及其在发病机制中的作用。我们首次报告了从黑猩猩和非洲绿猴分离出的一株STLV-1的全长前病毒序列。系统发育分析显示，HTLV-1a亚型中的辅助蛋白p12、p30和p13具有高度保守性。相反，一些非洲PTLV-1亚型的p12或p13开放阅读框缺失。对于亚洲亚型，猴毒株通常缺乏p12、p13或p30蛋白，而人毒株保留p30和p13的开放阅读框，但不保留p12的开放阅读框。为了评估一株缺乏p12、p13和p30开放阅读框的PTLV-1猴毒株的感染性，我们从一只自然感染的日本猕猴（Mfu：猕猴）构建了一个分子克隆，并将其与HTLV-1a进行比较。使用报告基因检测和酶联免疫吸附测定，我们发现其对Jurkat T细胞的感染性相似；然而，STLV-1 Mfu在单核细胞系THP-1中的感染性受损。此外，尽管HTLV-1/STLV-1碱性亮氨酸拉链因子（HBZ/SBZ）开放阅读框具有保守性，但源自HTLV-1a和非洲PTLV-1亚型的HBZ/SBZ蛋白比源自亚洲亚型的蛋白诱导TGF-β/Smad信号通路的激活明显更高。总体而言，我们的研究结果表明，PTLV-1亚型获得辅助蛋白可能赋予PTLV-1在包括人类在内的猿类感染期间的有利适应性。此外，在PTLV-1毒株中，HBZ/SBZ对TGF-β/Smad途径具有不同程度的活性；这一事实强调了病毒蛋白与宿主信号通路之间复杂的相互作用，可能影响不同物种中的病毒致病性。
