Sedohara Ayako, Koibuchi Tomohiko, Yamagishi Makoto, Koga Michiko, Arizono Kotaro, Ikeuchi Kazuhiko, Kikuchi Tadashi, Saito Makoto, Adachi Eisuke, Tsutsumi Takeya, Honma Daisuke, Araki Kazushi, Uchimaru Kaoru, Yotsuyanagi Hiroshi
Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
Front Microbiol. 2025 Apr 10;16:1581330. doi: 10.3389/fmicb.2025.1581330. eCollection 2025.
For the eradication of human immunodeficiency virus type 1 (HIV-1) provirus from people living with HIV-1, reactivation of latently HIV-1-infected cells is essential. Although several latency reversing agents have been identified, eradication of HIV-infected cells has been a challenge. Here, we investigated whether the novel enhancer of zeste homolog 1/2 (EZH1/2) dual inhibitor valemetostat/DS-3201/()-OR-S2 could efficiently reactivate latently HIV-1-infected cells and . People living with HIV-1 who were on suppressive combined antiretroviral therapy and with plasma HIV-1 virus levels consistently below 50 copies/mL were enrolled in this study. ACH2 cells were treated with valemetostat for 7-14 days and with suberoylanilide hydroxamic acid (SAHA). CD4 T cells were treated with valemetostat or the EZH2-selective inhibitors GSK126 and E7438 for 22 days alone or in combination with SAHA. expression in CD4 T cells was determined. Valemetostat more effectively induced mRNA expression in ACH-2 cells when administered for 14 days than when administered for 7 days. Valemetostat reversed latently HIV-l-infected CD4 T cells isolated from patients with HIV-1 and induced mRNA expression more potently than GSK126 and E7438. In addition, valemetostat induced mRNA expression more strongly when used in combination with SAHA compared with GSK126 and E7438. Expression levels of 21 hub genes were markedly increased after treatment with valemetostat. Gene Ontology analysis revealed that proteins encoded by these 21 genes were localized to the cell membrane and involved in the immune response. Kyoto Encyclopedia of Genes and Genomes enrichment pathway analysis showed that these 21 hub genes contributed to various signaling pathways, including the JAK-STAT signaling pathway. This study provides novel insights for the development of treatments to reactivate latently HIV-1-infected cells.
为了从人类免疫缺陷病毒1型（HIV-1）感染者体内根除HIV-1前病毒，潜伏感染HIV-1的细胞的重新激活至关重要。尽管已经鉴定出几种潜伏逆转剂，但根除HIV感染细胞仍是一项挑战。在此，我们研究了新型的zeste同源物1/2（EZH1/2）双重抑制剂瓦美司他/DS-3201/（）-OR-S2是否能有效重新激活潜伏感染HIV-1的细胞。本研究纳入了接受抑制性联合抗逆转录病毒治疗且血浆HIV-1病毒水平持续低于50拷贝/毫升的HIV-1感染者。ACH2细胞用瓦美司他处理7至14天，并使用辛二酰苯胺异羟肟酸（SAHA）处理。CD4 T细胞单独用瓦美司他或EZH2选择性抑制剂GSK126和E7438处理22天，或与SAHA联合处理。测定CD4 T细胞中的表达。与处理7天时相比，瓦美司他处理14天时更有效地诱导ACH-2细胞中mRNA表达。瓦美司他可逆转从HIV-1患者分离出的潜伏感染HIV-1的CD4 T细胞，并比GSK126和E7438更有效地诱导mRNA表达。此外，与GSK126和E7438相比，瓦美司他与SAHA联合使用时更强烈地诱导mRNA表达。用瓦美司他处理后，21个枢纽基因的表达水平显著增加。基因本体分析显示，这21个基因编码的蛋白质定位于细胞膜并参与免疫反应。京都基因与基因组百科全书富集通路分析表明，这21个枢纽基因参与了包括JAK-STAT信号通路在内的各种信号通路。本研究为开发重新激活潜伏感染HIV-1细胞的治疗方法提供了新的见解。
