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

子宫颈癌仍然是妇女发病和死亡的一个重要原因，特别是在艾滋病毒感染者中。 低收入和中等收入国家（LMIC），如南非。人乳头瘤病毒检测 (HPV)，宫颈癌的病原体显著改善了 在LMIC的护理点。然而，尽管高危HPV类型的持续存在是导致HPV感染的主要原因， 癌前宫颈上皮内瘤变2级和3级（CIN2+）和浸润性宫颈癌（ICC）， 它的检测具有较低的阳性预测值，因为只有一小部分HPV+妇女会进展到 CIN或ICC。因此，迫切需要对HPV阳性妇女进行"分诊"，以减少不必要的 治疗一旦确定了前驱病变，就可以通过消融或切除方法进行治疗， 取决于等级。这两种方法都有很大的复发风险。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志物， 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，特别是其局部微生物组。初步证据表明， 惰性乳杆菌的多样性和存在与CIN2+相关。L. iners拥有高度可变的 移动的基因库，含有甲基化酶和毒素，可能在宫颈癌进展中发挥作用。 病变阐明哪些分类群或基因是疾病状态的预测可以使发展， HPV+女性的辅助快速诊断。在这里，我们建议全面研究病毒-微生物群-宿主 相互作用，特别是HPV与下生殖道细菌和真菌之间的相互作用 与艾滋病毒阳性和阴性妇女的宫颈癌筛查相关。我们在哥伦比亚大学的研究小组有一个很长的- 与南非开普敦大学的长期和高效合作，我们与他们 开展了大量预防宫颈癌的临床研究。我们将利用样本和临床数据 已经收集到的数据。在目标1中，我们将定义宫颈阴道细菌是否 和真菌群落区分HPV感染的妇女谁有或没有CIN2+，分层 艾滋病状况。在目标2中，我们将测试基线时宫颈微生物分类群或分类群随时间的变化， 预测HPV +/CIN2+女性患者消融治疗后6个月或12个月的复发。这将告知哪些 患者需要更多的监测，并指导识别潜在的“辅助”治疗，以改善 通过减少治疗后疾病复发来提高筛查方案的有效性。在目标3中，我们将应用 宏基因组学用于识别预测宫颈癌的微生物基因标记和结构遗传变异 治疗失败。结合起来，我们的工作将为潜在的分流测试提供信息，以减少没有 宫颈疾病开始治疗，提高检测高危妇女的敏感性， 治疗失败，并产生机制的见解，以帮助指导辅助治疗的未来发展。

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.