病原体对宿主疾病的影响只能在涵盖整个病理过程的样本中进行研究。持续的致癌人乳头瘤病毒（HPV）感染是宫颈癌的最常见原因。在此，我们研究了HPV诱导的宿主表观基因组广泛变化在细胞学异常发展之前。利用来自无疾病女性的宫颈样品甲基化阵列数据，分别对有或没有致癌HPV感染，我们开发了WID（女性癌症风险识别）-HPV，该标志反映了与高危HPV菌株相关的正常宿主表观基因组变化（在无疾病的女性中AUC = 0.78，95％CI：0.72-0.85）。 通过疾病发展观察HPV相关变化，发现有轻微细胞学改变（宫颈上皮内瘤变1/2级，CIN1 / 2）的HPV感染女性，但惊人的是没有发现癌前改变或宫颈癌（CIN3 +）的增多WID-HPV指数，表明WID-HPV可以反映出成功的病毒清除反应，这在癌症发展中是缺乏的。进一步研究发现，WID-HPV与细胞凋亡呈正相关（ρ = 0.48; p <0.001），与表观遗传年龄呈负相关（ρ = -0.43; p <0.001）。综上，我们的数据表明WID-HPV捕获了与HPV感染细胞的凋亡清除反应相关的反应。这种反应可能会随着感染细胞底层复制年龄的增加而减弱或丧失，从而导致癌症的进展。本文受版权保护。版权所有。

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic Human Papilloma Virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC=0.78, 95% CI: 0.72-0.85, in non-diseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ=0.48; p<0.001) and negatively associated with epigenetic replicative age (ρ=-0.43; p<0.001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.