Background

Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections. However, only a small percentage of high-risk (HR) HPV infections progress to cervical precancer and cancer. In this study, we investigated the role of the cervicovaginal microbiome (CVM) in the natural history of HR-HPV.

Methods

This study was nested within the placebo arm of the Costa Rica HPV Vaccine Trial that included women aged 18–25 years of age. Cervical samples from two visits of women with an incident HR-HPV infection (n = 273 women) were used to evaluate the prospective role of the CVM on the natural history of HR-HPV. We focus specifically on infection clearance, persistence, and progression to cervical intraepithelial neoplasia grade 2 and 3 (CIN2+). The CVM was characterized by amplification and sequencing the bacterial 16S V4 rRNA gene region and the fungal ITS1 region using an Illumina MiSeq platform. OTU clustering was performed using QIIME2. Functional groups were imputed using PICRUSt and statistical analyses were performed using R.

Results

At Visit 1 (V1) abundance of Lactobacillus iners was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis (LDA)>4.0), whereas V1 Gardnerella was the dominant biomarker for HR-HPV progression (LDA>4.0). At visit 2 (V2), increased microbial Shannon diversity was significantly associated with progression to CIN2+ (p = 0.027). Multivariate mediation analysis revealed that the positive association of V1 Gardnerella with CIN2+ progression was due to the increased cervicovaginal diversity at V2 (p = 0.040). A full multivariate model of key components of the CVM showed significant protective effects via V1 genus Lactobacillus, OR = 0.41 (0.22–0.79), V1 fungal diversity, OR = 0.90 (0.82–1.00) and V1 functional Cell Motility pathway, OR = 0.75 (0.62–0.92), whereas V2 bacterial diversity, OR = 1.19 (1.03–1.38) was shown to be predictive of progression to CIN2+.

Conclusion

This study demonstrates that features of the cervicovaginal microbiome are associated with HR-HPV progression in a prospective longitudinal cohort. The analyses indicated that the association of Gardnerella and progression to CIN2+ may actually be mediated by subsequent elevation of microbial diversity. Identified features of the microbiome associated with HR-HPV progression may be targets for therapeutic manipulation to prevent CIN2+.

Trial registration

ClinicalTrials.gov NCT00128661.

中文翻译：

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一项纵向研究显示宫颈阴道微生物组和HPV的自然病史。

背景

人乳头瘤病毒（HPV）感染是最常见的性传播感染之一。但是，只有极少数的高危（HR）HPV感染进展为宫颈癌和癌症。在这项研究中，我们调查了宫颈阴道微生物组（CVM）在HR-HPV自然史中的作用。

方法

这项研究嵌套在哥斯达黎加HPV疫苗试验的安慰剂组中，该试验包括18至25岁的女性。使用两次来访的患有HR-HPV感染的妇女（n = 273名妇女）的宫颈样本来评估CVM对HR-HPV的自然病史的预期作用。我们特别关注感染清除，持久性以及进展为2级和3级宫颈上皮内瘤变（CIN2 +）。通过使用Illumina MiSeq平台对细菌16S V4 rRNA基因区和真菌ITS1区进行扩增和测序来表征CVM。使用QIIME2进行OTU聚类。使用PICRUSt估算功能组，并使用R进行统计分析。

结果

在第1次就诊（V1）时，乳酸杆菌的丰富与清除事件HR-HPV感染有关（线性判别分析（LDA）> 4.0），而V1 Gardnerella是HR-HPV进展的主要生物标志物（LDA> 4.0）。在第2次访问（V2）时，微生物香农多样性的增加与CIN2 +的进展显着相关（p = 0.027）。多元中介分析显示，V1 Gardnerella与CIN2 +进展呈正相关是由于V2处宫颈阴道多样性增加（p = 0.040）。CVM关键组件的完整多元模型显示了通过V1乳杆菌属产生的显着保护作用，或= 0.41（0.22-0.79），V1真菌多样性，或= 0.90（0.82-1.00）和V1功能性细胞运动途径，或= 0.75（0.62-0.92），而V2细菌多样性，或= 1.19（1.03-1.38） ）被证明可以预测CIN2 +的进展。

结论

这项研究表明在预期的纵向队列中宫颈阴道微生物组的特征与HR-HPV进展有关。分析表明，加德纳氏菌与向CIN2 +的进展可能实际上是由随后微生物多样性的升高介导的。与HR-HPV进展相关的微生物组的特征可能是预防CIN2 +的治疗性操作的目标。

试用注册

ClinicalTrials.gov NCT00128661。