近日，澳大利亚沃尔特和伊丽莎·霍尔医学研究所教授Marc Pellegrini及其研究组揭示了联合抗逆转录病毒治疗和MCL-1抑制可减轻体内HTLV-1感染。相关论文于2025年7月10日发表在《细胞》杂志上。
研究团队建立并表征了HTLV-1c感染的人源化motheme模型，发现HTLV-1c疾病似乎比流行的HTLV-1亚型-a （HTLV-1a）更具侵袭性，这可能是HTLV-1c感染相关肺部并发症风险增加的基础。临床相关剂量的替诺福韦和多替格拉韦联合抗逆转录病毒治疗可显著降低体内HTLV-1c传播和疾病进展。单细胞RNA测序（scRNA-seq）和细胞内流式细胞术发现HTLV-1c感染导致体内感染细胞的内在凋亡失调。药物抑制BH3模拟化合物对MCL-1，而不是BCL-2， BCL-XL或BCL-w，在体外和体内杀死HTLV-1c感染的细胞，并在小鼠中与替诺福韦和dolutegravir联合使用时显着延迟疾病进展。他们的数据表明，抗逆转录病毒联合MCL-1拮抗剂可能是一种有效的、临床相关的、潜在的治疗HTLV-1c的策略。
研究人员表示，本研究探讨了人类嗜T淋巴细胞病毒1亚型- c （HTLV-1c）感染的预防和治疗药物。
附：英文原文
Title: Combination antiretroviral therapy and MCL-1 inhibition mitigate HTLV-1 infection in vivo
Author: James P. Cooney, Ashley Hirons, Natasha Jansz, Cody C. Allison, Peter Hickey, Charis E. Teh, Tania Tan, Laura F. Dagley, Jumana Yousef, David Yurick, Georges Khoury, Simon P. Preston, Philip Arandjelovic, Kathryn C. Davidson, Lewis J. Williams, Stefanie M. Bader, Le Wang, Reet Bhandari, Liana Mackiewicz, Merle Dayton, William Clow, Geoffrey J. Faulkner, Daniel H. Gray, Lloyd Einsiedel, Damian F.J. Purcell, Marcel Doerflinger, Marc Pellegrini
Issue&Volume: 2025-07-10
Abstract: This study investigated preventative and therapeutic agents against human T cell lymphotropic virus type-1 subtype-C (HTLV-1c) infection. We established and characterized a humanized mouse model of HTLV-1c infection and identified that HTLV-1c disease appears slightly more aggressive than the prevalent HTLV-1 subtype-A (HTLV-1a), which may underpin increased risk for infection-associated pulmonary complications in HTLV-1c. Combination antiretroviral therapy with tenofovir and dolutegravir at clinically relevant doses significantly reduced HTLV-1c transmission and disease progression in vivo. Single-cell RNA sequencing (scRNA-seq) and intracellular flow cytometry identified that HTLV-1c infection leads to dysregulated intrinsic apoptosis in infected cells in vivo. Pharmacological inhibition using BH3 mimetic compounds against MCL-1, but not BCL-2, BCL-XL, or BCL-w, killed HTLV-1c-infected cells in vitro and in vivo and significantly delayed disease progression when combined with tenofovir and dolutegravir in mice. Our data suggest that combination antiretroviral therapy with MCL-1 antagonism may represent an effective, clinically relevant, and potentially curative strategy against HTLV-1c.
DOI: 10.1016/j.cell.2025.06.023
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00689-0