Impact of HIV, oral microbiome and mycobiome on oral HPV persistence

HIV、口腔微生物组和真菌组对口腔 HPV 持久性的影响

• 批准号: 10683323
• 负责人: Robert D Burk
• 金额: $ 82.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683323
• 关键词: 16S ribosomal RNA sequencing; Actinomyces; Activities of Daily Living; Address; Affect; Alcohol consumption; Bacteria; Bacterial Infections; Biological Assay; Biological Markers; CD4 Lymphocyte Count; Candida; Cohort Studies; Communities; Coupling; Cutaneous; Data; Dental; Detection; Disease; Enrollment; Ethnic Origin; Etiology; Evaluation; Exhibits; Female; Frequencies; Genes; HIV; HIV Infections; HPV-High Risk; Head and Neck Cancer; Human Papilloma Virus Vaccination; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papillomavirus 16; Immune; Immune response; Immune system; Immunity; Incidence; Individual; Infection; Inflammation; Lesion; Longitudinal Studies; Malassezia; Malignant Neoplasms; Measures; Mediation; Metagenomics; Methods; Morbidity - disease rate; Mouth Diseases; Mycoses; Natural History; Oncogenic; Oral; Oral Characters; Oral cavity; Oral health; Organism; Outcome; Papilloma; Participant; Pathway interactions; Patients; Persons; Porphyromonas; Predisposition; Prevalence; Prevotella; Protein Analysis; Public Health; RNA; Race; Research Design; Ribosomal RNA; Risk; Risk Factors; Saliva; Sampling; Sex Behavior; Shotguns; Smoking; Smoking Behavior; Smoking History; Specimen; Structure; Taxonomy; Time; Tobacco smoking behavior; Tooth structure; United States; Variant; Viral Load result; Virulence Factors; Work; Xerostomia; antiretroviral therapy; cancer risk; cohort; cytokine; fungus; high risk; innovation; male; malignant mouth neoplasm; malignant oropharynx neoplasm; marijuana use; metagenomic sequencing; microbial; microbiome; mycobiome; neoplastic; next generation sequencing; novel; oral HPV; oral HPV infection; oral lesion; oral microbiome; oral wart; population based; response; saliva sample; therapy adherence; therapy duration; virome

ABSTRACT Oral human papillomavirus (HPV) infections and HPV-associated papillomas and cancers continue to rise, especially in people living with HIV (PLWH). Specifically, rates of HPV-associated oral and oropharyngeal cancer are increasing at an alarming rate. Using large population-based longitudinal studies, our work indicated an increased risk of oral lesions and head and neck cancers with not only HPV16, but unexpectedly cutaneous beta and gamma HPVs as well. Studying risk factors, we identified an interaction between smoking and HIV serostatus with increased prevalence of oral high-risk alpha and beta-HPV detection. In addition to oral HPV, HIV affects the composition of the oral microbiome, which has also been associated with increased susceptibility to oral HPV infection, persistence, and progression to HPV-driven cancer. Taken together, these findings indicate a continuing public health concern of HPV-related oral diseases for PLWH. The proposed study will leverage repeat oral saliva samples collected from N=2046 male and female PLWH, and N=1334 HIV[-] individuals enrolled in the MACS-WIHS Combined Cohort Study (MWCSS). Specifically, we will investigate the associations between the oral microbiome and mycobiome and risk of acquisition and persistence of high-risk alpha, beta, and gamma oral HPV. The scientific premise of the study is that alterations in the oral microbiome / mycobiome resulting from HIV and smoking influence oral HPV natural history. We will use novel sequencing methods developed by our team, including next generation sequencing and metagenomics, to profile the HPV virome (alpha, beta, and gamma HPV), oral bacterial (16S rRNA) and fungal communities (using a recently developed ITS1 assay with increased sensitivity for Candida developed in the Burk lab), functional gene capacity (determined from shotgun metagenomic sequencing), and cytokine profiles (derived from oral saliva protein analyses). Differences in the oral microbiome / mycobiome between PLWH and HIV[-] individuals will be assessed, as well as markers of HIV disease and smoking, with respect to oral HPV persistence. Taking advantage of serial samples collected in MWCCS participants, we will characterize oral microbiome / mycobiome changes over time in response to CD4 count and HIV RNA level, smoking, and the oral microbiome / mycobiome to address the following specific aims: 1) Determine the combined effects of HIV and smoking on risk of oral HPV persistence; 2) Study the associations between the oral microbiome / mycobiome and risk of oral HPV persistence; 3) Characterize the microbial function and oral inflammation/immune pathways associated with risk of oral HPV persistence. We hypothesize that the oral microbiome and mycobiome influenced by HIV and smoking exhibit significantly higher proportions of virulence factors, which in turn dysregulate the oral barrier immunity and integrity, facilitating persistence of oral high-risk HPV types associated with increased risks for oral and oropharyngeal cancer.

抽象的 口腔人乳头瘤病毒 (HPV) 感染以及 HPV 相关乳头状瘤和癌症持续上升， 尤其是艾滋病毒感染者（PLWH）。具体而言，HPV 相关口腔和口咽部感染率 癌症正在以惊人的速度增加。通过基于大规模人群的纵向研究，我们的工作 表明不仅 HPV16 会增加口腔病变和头颈癌的风险，而且出乎意料的是 皮肤 β 和 γ HPV 也是如此。通过研究危险因素，我们发现吸烟与吸烟之间存在相互作用 HIV 血清状态随着口腔高危 α 和 β-HPV 检测患病率的增加而增加。此外 口腔 HPV、HIV 会影响口腔微生物群的组成，这也与口腔微生物群的增加有关。 对口腔 HPV 感染的易感性、持续性以及 HPV 驱动的癌症的进展。综合起来，这些 研究结果表明，艾滋病毒感染者与 HPV 相关的口腔疾病一直是公众健康关注的焦点。拟议的 研究将利用从 N=2046 名男性和女性 PLWH 以及 N=1334 名患者中重复采集的口腔唾液样本 HIV[-] 个体参加了 MACS-WIHS 联合队列研究 (MWCSS)。具体来说，我们将 研究口腔微生物组和真菌组之间的关联以及获得和感染的风险 高危 α、β 和 γ 口腔 HPV 的持续存在。该研究的科学前提是 HIV 和吸烟引起的口腔微生物组/真菌组的改变会影响口腔 HPV 自然感染 历史。我们将使用我们团队开发的新颖测序方法，包括下一代测序 和宏基因组学，以分析 HPV 病毒组（α、β 和 γ HPV）、口腔细菌（16S rRNA）和 真菌群落（使用最近开发的 ITS1 测定法，该测定法对念珠菌的敏感性更高，开发于 Burk 实验室）、功能基因容量（通过鸟枪法宏基因组测序确定）和细胞因子 概况（来自口腔唾液蛋白质分析）。口腔微生物组/真菌组之间的差异 将对艾滋病病毒感染者和艾滋病毒[-]个体以及艾滋病毒疾病和吸烟的标志物进行评估 口腔 HPV 持续存在。利用 MWCCS 参与者收集的系列样本，我们将 表征口腔微生物组/真菌组随时间的变化以响应 CD4 计数和 HIV RNA 水平， 吸烟和口腔微生物组/真菌组，以实现以下具体目标：1) 确定 HIV 和吸烟对口腔 HPV 持续存在风险的综合影响； 2）研究之间的关联 口腔微生物组/真菌组和口腔 HPV 持续存在的风险； 3)表征微生物功能和口腔 与口腔 HPV 持续存在风险相关的炎症/免疫途径。我们假设口头 受艾滋病毒和吸烟影响的微生物组和真菌组表现出明显更高的毒力比例 因素，进而失调口腔屏障免疫和完整性，促进口腔高风险的持续存在 HPV 类型与口腔癌和口咽癌风险增加相关。