Akter Dilruba, Biswas Juthi, Moradpour Shima, Carter Meghan F, Miller Michael J, Thiele Dennis J, Murphy Eain A, O'Connor Christine M, Moffat Jennifer F, Chan Gary C
Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
Sisu Pharma, Inc., San Diego, CA, 92121, USA.
Antiviral Res. 2025 May;237:106150. doi: 10.1016/j.antiviral.2025.106150. Epub 2025 Mar 25.
FDA-approved antivirals against HCMV have several limitations, including only targeting the later stages of the viral replication cycle, adverse side effects, and the emergence of drug-resistant strains. Antivirals targeting host factors specifically activated within infected cells and necessary for viral replication could address the current drawbacks of anti-HCMV standard-of-care drugs. In this study, we found HCMV infection stimulated the activation of the stress response transcription factor heat shock transcription factor 1 (HSF1). HCMV entry into fibroblasts rapidly increased HSF1 activity and subsequent relocalization from the cytoplasm to the nucleus, which was maintained throughout viral replication and in contrast to the transient burst of activity induced by canonical heat shock. Prophylactic pharmacological inhibition or genetic depletion of HSF1 prior to HCMV infection attenuated the expression of all classes of viral genes, including immediate early (IE) genes, and virus production, suggesting HSF1 promotes the earliest stages of the viral replication cycle. Therapeutic treatment with SISU-102, an HSF1 inhibitor tool compound, after IE expression also reduced the levels of L proteins and progeny production, suggesting HSF1 regulates multiple steps along the HCMV replication cycle. Leveraging a newly developed human skin xenograft transplant murine model, we found prophylactic treatment with SISU-102 significantly attenuated viral replication in transplanted human skin xenografts as well as viral dissemination to distal sites. These data demonstrate HCMV infection rapidly activates and relocalizes HSF1 to the nucleus to promote viral replication, which can be exploited as a host-directed antiviral strategy.
美国食品药品监督管理局（FDA）批准的抗人巨细胞病毒（HCMV）药物有几个局限性，包括仅针对病毒复制周期的后期阶段、有不良副作用以及出现耐药菌株。靶向在受感染细胞内特异性激活且病毒复制所必需的宿主因子的抗病毒药物可以解决当前抗HCMV标准护理药物的缺点。在本研究中，我们发现HCMV感染刺激了应激反应转录因子热休克转录因子1（HSF1）的激活。HCMV进入成纤维细胞迅速增加了HSF1的活性，并随后从细胞质重新定位到细胞核，这种定位在整个病毒复制过程中都得以维持，这与经典热休克诱导的短暂活性爆发形成对比。在HCMV感染之前对HSF1进行预防性药理抑制或基因敲除可减弱所有类别的病毒基因的表达，包括立即早期（IE）基因，以及病毒产生，这表明HSF1促进病毒复制周期的最早阶段。在IE表达后用HSF1抑制剂工具化合物SISU - 102进行治疗也降低了L蛋白的水平和子代产生，这表明HSF1调节HCMV复制周期的多个步骤。利用新开发的人皮肤异种移植小鼠模型，我们发现用SISU - 102进行预防性治疗可显著减弱移植的人皮肤异种移植物中的病毒复制以及病毒向远端部位的传播。这些数据表明HCMV感染迅速激活HSF1并将其重新定位到细胞核以促进病毒复制，这可被用作一种宿主导向的抗病毒策略。
