The role of the microbiome in HPV-associated cervical cancer in women with HIV

宫颈癌仍然是妇女发病率和死亡率的重要原因，特别是在感染艾滋病毒的妇女中。 低收入和中等收入国家的妇女，如南非。人乳头瘤病毒检测 宫颈癌的病因(HPV)显著改进了筛查和治疗方法 LMIC的护理点。然而，尽管高危HPV类型的持续存在是导致 癌前病变宫颈上皮内瘤变2级和3级(CIN2+)和浸润性宫颈癌(ICC)， 它的检测具有很低的阳性预测价值，因为只有一小部分HPV+女性会进展到 CIN或ICC。因此，迫切需要对HPV阳性的妇女进行分类，以减少不必要的 治疗。一旦确定了前驱病变，就用消融或切除的方法进行治疗， 视年级而定。这两种方法都有显著的复发风险。更好地预测高风险 需要在治疗时复发以及治疗后复发的潜在标记物 降低宫颈癌的发病率。促进癌症进展的关键因素可能存在于 宫颈环境，特别是其当地的微生物群。初步证据表明，增加的细菌 乳杆菌的多样性和内源乳杆菌的存在与CIN2+有关。L.iners藏匿着高度可变的 可移动的遗传谱系，包含可能在宫颈病变进展中起作用的甲基酶和毒素 损伤。阐明哪些分类群或基因可以预测疾病状态，可以使 HPV阳性妇女的辅助快速诊断。在这里，我们建议对病毒-微生物-宿主进行综合研究 相互作用，特别是HPV与下生殖道共生细菌和真菌之间的相互作用 与艾滋病毒阳性和艾滋病毒感染妇女的宫颈癌筛查相关。我们在哥伦比亚大学的团队有一个很长的- 与南非开普敦大学的长期和富有成效的合作，我们 承担了预防宫颈癌的大型临床研究。我们将利用样本和临床数据 已经从最近的两项研究中收集到。在目标1中，我们将定义宫颈阴道细菌 真菌群落区分感染HPV的妇女是否有CIN2+，分层 根据艾滋病病毒的状况。在目标2中，我们将测试宫颈微生物分类群是否处于基线，或分类群随时间的变化， 预测HPV+/CIN2+女性消融治疗后6或12个月的复发。这将通知哪位 患者需要更多的监测，并指导识别潜在的“辅助”疗法以改进 通过减少治疗后复发疾病的筛查计划的效果。在目标3中，我们将应用 微基因组学用于确定预测宫颈癌的微生物基因标记和结构遗传变异 治疗失败。总而言之，我们的工作将为潜在的分诊测试提供信息，以减少没有 宫颈疾病开始治疗，提高检测高危妇女的敏感度 治疗失败，并产生机制的见解，以帮助指导未来的辅助治疗的发展。

Cervical cancer remains an important cause of morbidity and mortality in women, in particular in HIV-infected women in low and middle-income countries (LMIC), such as South Africa. Testing for human papilloma virus (HPV), the etiological agent of cervical cancer has significantly improved screen-and-treat approaches at the point of care in LMIC. However, although persistence of high-risk HPV types is the primary cause of precancerous cervical intraepithelial neoplasia grade 2 and 3 (CIN2+) and invasive cervical carcinoma (ICC), its detection has a low positive predictive value, as only a small proportion of HPV+ women will progress to CIN or ICC. Therefore, there is a compelling need for “triaging” HPV-positive women, to reduce unnecessary treatment. Once precursor lesions are identified, they are treated by either ablative or excisional methods, depending on grade. Both of these methods have significant recurrence risk. Better predictors of high-risk recurrences at the time of treatment as well as potential markers for recurrence post-treatment are needed to drive down the incidence of cervical cancer. The key factors that promote cancer progression likely reside in the cervical environment, notably its local microbiome. Preliminary evidence suggests that increased bacterial diversity and the presence of Lactobacillus iners are associated with CIN2+. L. iners harbors a highly variable mobile genetic repertoire, containing methylases and toxins that may play a role in progression of cervical lesions. Elucidating which taxa or genes are predictive of disease state could enable the development of adjunct rapid diagnostics in HPV+ women. Here we propose to comprehensively study virus-microbiota-host interactions, specifically the interaction between HPV and lower genital tract commensal bacteria and fungi relevant to cervical cancer screening in HIV+ and HIV- women. Our group at Columbia University has a long- standing and highly-productive collaboration with the University of Cape Town, South Africa, with whom we have undertaken large clinical studies of cervical cancer prevention. We will leverage samples and clinical data already collected from two of these recent studies. In Aim 1, we will define whether the cervicovaginal bacterial and fungal communities distinguish between HPV-infected women who have or do not have CIN2+, stratified by HIV status. In Aim 2, we will test whether cervical microbial taxa at baseline, or changes in taxa over time, predict recurrence after ablative therapy at 6 or 12 months in women with HPV+/CIN2+. This will inform which patients require more monitoring, and guide the identification of potential “adjuvant” therapies to improve efficacy of screening programs by reducing recurrent disease after treatment. In Aim 3 we will apply metagenomics to identify microbial gene markers and structural genetic variants that predict cervical cancer treatment failure. Combined, our work will inform potential triage tests to reduce the number of women without cervical disease beginning treatment, increase the sensitivity for detecting women who are at high risk of treatment failure, and yield mechanistic insights to help guide the future development of adjunct therapeutics.