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）感染以及与HPV相关的乳头状瘤和癌症不断上升， 特别是在患有艾滋病毒（PLWH）的人中。具体而言，与HPV相关的口腔和口咽率 癌症以惊人的速度增加。使用大型基于人群的纵向研究，我们的工作 表明口腔病变的风险增加，不仅具有HPV16，而且出乎意料 皮肤β和伽马HPV也是如此。研究风险因素，我们确定了吸烟之间的相互作用 和HIV血清，口服高危α和β-HPV检测的患病率增加。此外 口服HPV，HIV影响口服微生物组的组成，这也与增加有关 口服HPV感染，持久性和对HPV驱动癌症的敏感性。总的来说，这些 调查结果表明，与HPV相关的口腔疾病对PLWH的持续关注。提议 研究将利用从n = 2046雄性和女性PLWH收集的重复口服唾液样本，n = 1334 HIV [ - ]参加了Macs-Wihs合并队列研究（MWCSS）的个体。具体来说，我们会的 调查口腔微生物组与并非生物组之间的关联以及获取的风险和 高风险α，beta和伽玛口服HPV的持久性。该研究的科学前提是 艾滋病毒和吸烟会影响口服HPV自然的口服微生物组 /真菌症的改变 历史。我们将使用团队开发的新型测序方法，包括下一代测序 和宏基因组学，以介绍HPV病毒素（alpha，beta和Gamma HPV），口服细菌（16S rRNA）和 真菌群落（使用最近开发的ITS1分析，对念珠菌的敏感性提高 Burk Lab），功能基因能力（由shot弹枪元基因组测序确定）和细胞因子 剖面（源自口服唾液蛋白分析）。口服微生物组 / mycobiome的差异 将评估PLWH和HIV [ - ]个体以及HIV疾病和吸烟的标志 口服HPV持久性。利用在MWCCS参与者中收集的串行样本的优势，我们将 表征口服微生物组 /真菌组随着时间的流逝而变化，响应CD4计数和HIV RNA水平， 吸烟和口服微生物组 / mycobiome以解决以下特定目的：1）确定 艾滋病毒和吸烟对口服HPV持久性风险的综合作用； 2）研究 口服微生物组 / mycobiome和口服HPV持久性的风险； 3）表征微生物功能和口服 与口服HPV持久性风险相关的炎症/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 因素反过来使口腔屏障免疫和完整性失调，促进口服高风险的持久性 HPV类型与口服和口咽癌风险增加有关。