Human cytomegalovirus (HCMV) is a ubiquitous pathogen that latently infects hematopoietic cells and has the ability to reactivate when triggered by immunological stress. This reactivation causes significant morbidity and mortality in immune-deficient patients, who are unable to control viral dissemination. While a competent immune system helps prevent clinically detectable viremia, a portrait of the factors that induce reactivation following the proper cues remains incomplete. Our understanding of the complex molecular mechanisms underlying latency and reactivation continues to evolve. We previously showed the HCMV-encoded G protein-coupled receptor US28 is expressed during latency and facilitates latent infection by attenuating the activator protein-1 (AP-1) transcription factor subunit, c-fos, expression and activity. We now show AP-1 is a critical component for HCMV reactivation. Pharmacological inhibition of c-fos significantly attenuates viral reactivation. In agreement, infection with a virus in which we disrupted the proximal AP-1 binding site in the major immediate early (MIE) enhancer results in inefficient reactivation compared to WT. Concomitantly, AP-1 recruitment to the MIE enhancer is significantly decreased following reactivation of the mutant virus. Furthermore, AP-1 is critical for derepression of MIE-driven transcripts and downstream early and late genes, while immediate early genes from other loci remain unaffected. Our data also reveal MIE transcripts driven from the MIE promoter, the distal promoter, and the internal promoter, iP2, are dependent upon AP-1 recruitment, while iP1-driven transcripts are AP-1–independent. Collectively, our data demonstrate AP-1 binding to and activation of the MIE enhancer is a key molecular process controlling reactivation from latency.

人类巨细胞病毒（HCMV）是一种普遍存在的病原体，可潜伏感染造血细胞，并具有免疫应激触发时能够重新激活的能力。这种重新激活会导致无法控制病毒传播的免疫缺陷患者的大量发病率和死亡率。称职的免疫系统有助于预防临床上可检测到的病毒血症，但根据正确的提示，诱导再激活的因素的肖像仍然不完整。我们对潜伏期和再激活背后的复杂分子机制的理解在不断发展。我们先前显示了HCMV编码的G蛋白偶联受体US28在潜伏期表达，并通过减弱激活蛋白-1（AP-1）转录因子亚基，c-fos，表达和活性促进潜伏感染。我们现在显示AP-1是HCMV重新激活的关键组成部分。c-fos的药理抑制作用显着减弱了病毒的再激活。一致地，与WT相比，感染病毒后我们破坏了主要的早期早期（MIE）增强子中的近端AP-1结合位点，导致重新激活效率低下。同时，突变病毒重新激活后，AP-1向MIE增强子的募集显着减少。此外，AP-1对于抑制MIE驱动的转录物和下游早期和晚期基因非常重要，而来自其他基因座的立即早期基因仍然不受影响。我们的数据还揭示了由MIE启动子，远端启动子和内部启动子iP2驱动的MIE转录物取决于AP-1募集，而iP1驱动的转录物与AP-1无关。总的来说，我们的数据表明，AP-1与MIE增强剂的结合和激活是控制潜伏期重新激活的关键分子过程。