Cross Sectional Association of the Oral Microbiota and the Inflammasome with Oral HPV among HIV+ Adults

HIV 成人口腔微生物群和炎症小体与口腔 HPV 的横断面关联

• 批准号: 10305164
• 负责人: Josue Perez-Santiago
• 金额: $ 17.35万
• 依托单位: COMPREHENSIVE CANCER CENTER/ UNIV/PR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-07 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305164
• 关键词: 16S ribosomal RNA sequencing; Accounting; Adult; Affect; Behavioral; Bioinformatics; CASP1 gene; Cause of Death; Characteristics; Chemoresistance; Chronic; Cleaved cell; Clinic; Clinical; Collection; Communities; Complex; Cross-Sectional Studies; Development; Disease; Dysplasia; Early identification; Ecology; Enzyme-Linked Immunosorbent Assay; Epidemiology; Equipment and supply inventories; Evaluation; Future; Gemella; Genes; Genotype; Goals; HIV; HIV Infections; Hemophilus; High Prevalence; Hispanics; Homeostasis; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; IL8 gene; Immune; Immune response; Immune system; Immunity; Impairment; Incidence; Individual; Inflammasome; Inflammation; Inflammatory; Interferon Type II; Interleukin-1 beta; Interleukin-6; Intervention; Lactobacillus; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Microbe; Microbiology; Natural History; Neoplasm Metastasis; Oral; Oral Characters; Oral cavity; Oral health; Participant; Pathogenesis; Patient Recruitments; Patients; Peptostreptococcus; Periodontal Diseases; Periodontitis; Play; Porphyromonas; Predisposition; Prevalence; Prevention strategy; Preventive; Preventive Health Services; Prevotella; Prognosis; Proteins; Public Health; Puerto Rican; Puerto Rico; Questionnaires; Recombinant DNA; Risk; Risk Factors; Role; STI prevention; Saliva; Sexually Transmitted Diseases; Signal Transduction; Streptococcus; TNF gene; Taxonomy; Testing; Therapeutic; Transcriptional Activation; Vaginal Human Papilloma Virus; Viral; Western Blotting; Woman; Work; antiretroviral therapy; base; biomarker discovery; cancer prevention; cancer risk; carcinogenesis; dysbiosis; early detection biomarkers; genetic variant; health disparity; high risk; high risk population; human microbiota; inflammatory marker; malignant oropharynx neoplasm; men; microbial; microbiome; mouth squamous cell carcinoma; novel; oral HPV; oral HPV infection; oral carcinogenesis; oral microbial community; oral microbiome; personalized medicine; personalized therapeutic; premalignant; protein biomarkers; protein complex; recruit; saliva sample; screening guidelines; social determinants; sociodemographics; socioeconomic disadvantage; surveillance strategy; targeted biomarker; transmission process; treatment response; tumor growth; tumor progression; vaginal infection; virology

PROJECT SUMMARY/ABSTRACT HPV-infection is the most common sexually transmitted disease (STI), and it accounts for 70% of oropharyngeal cancers. People living with HIV (PLWH) are disproportionately affected by HPV and are also at an increased risk of cancer development, even with suppressive antiretroviral therapy (ART), suggesting that ART may not fully recover oral HPV-specific immunity. Therefore, understanding other underlying factors that could facilitate the transmission and persistence of HPV in PLWH is crucial for the development of cancer prevention and surveillance strategies, and reduce the burden of HPV-associated malignancies in PLWH. The oral microbiota and inflammasome protein complex are essential factors for maintaining immune homeostasis factors, which are altered by HIV infection and have been observed in the pathogenesis of oropharyngeal cancer. Thus they represent novel targets for biomarker discovery and therapeutics. Our long-term goal is to investigate how these factors could contribute to immune dysregulation, and may affect the natural history of oral HPV infection in PLWH, in order to establish a set of early detection markers for HPV-related malignancies and personalized treatment interventions. We hypothesize that dysbiosis of the oral microbiome and inflammasome dysregulation can be risk factors for HPV-related complications and can contribute to the dampening the immune system promoting subsequent inflammation in PLWH. This cross-sectional study plans to recruit 200 virologically suppressed PLWH (men and women ≥21 and <49 years old) from a community-based organization, Puerto Rico (PR) CONCRA, that offers preventive and health services specialized in the treatment of the HIV and STI. PLWH who attends PR CONCRA constitute a unique high-risk group where the prevalence of both HIV and oral HPV infection is higher, allowing our team of experts in HIV, HPV, epidemiology, microbiology, oral health and bioinformatics to establish these relationships with high efficiency. The specific aims of this proposal are: (1) to characterize the oral microbiota in saliva and investigate its relationship with HPV status and HPV genotypes, and (2) to determine the association between the levels of inflammasome proteins (NLRP3, AIM2, and caspase- 1, IL-1β and cleaved IL-1β) and inflammation markers (IL-1β, IL-6, IL-8, TNF-α, IFN-γ) with oral HPV infection and HPV genotypes. After collection of saliva samples, participants will undergo oral health evaluations. Sociodemographic, behavioral, clinical characteristics, and risk factors will be collected through a questionnaire. Participants will be on stable, suppressive ART for at least 6 months to minimize inflammatory signals due to HIV active replication. We will characterize the oral microbiota by sequencing the 16S rDNA gene and HPV genotypes by PCR. Inflammasome proteins and inflammatory markers will be measured by Western Blot and multiplex ELISA respectively.

项目概要/摘要 HPV 感染是最常见的性传播疾病 (STI)，占口咽部感染的 70% 癌症。艾滋病毒感染者 (PLWH) 受 HPV 的影响尤为严重，而且风险也更高 即使采用抑制性抗逆转录病毒疗法 (ART)，癌症的发展也可能会受到影响，这表明 ART 可能无法完全 恢复口腔HPV特异性免疫力。因此，了解其他可以促进 HPV 在 PLWH 中的传播和持续存在对于癌症预防和治疗的发展至关重要 监测策略，并减少 PLWH 中 HPV 相关恶性肿瘤的负担。口腔微生物群 和炎性体蛋白复合物是维持免疫稳态的重要因素，它们是 因 HIV 感染而改变，并在口咽癌的发病机制中观察到。因此他们 代表生物标志物发现和治疗的新靶点。我们的长期目标是研究这些 因素可能导致免疫失调，并可能影响口腔 HPV 感染的自然史 PLWH，为了建立一套HPV相关恶性肿瘤的早期检测标志物和个性化 治疗干预。我们假设口腔微生物群失调和炎症小体失调 可能是 HPV 相关并发症的危险因素，并可能导致免疫系统受到抑制 促进感染者随后的炎症反应。这项横断面研究计划招募 200 名病毒学研究人员 来自波多黎各社区组织的抑制艾滋病病毒感染者（男性和女性，≥21 岁和 <49 岁） (PR) CONCRA，提供专门治疗艾滋病毒和性传播感染的预防和保健服务。艾滋病病毒感染者 参加 PR CONCRA 的人构成了一个独特的高危群体，其中 HIV 和口腔 HPV 的流行率 感染率更高，这使得我们的 HIV、HPV、流行病学、微生物学、口腔健康和 生物信息学可以高效地建立这些关系。本提案的具体目标是：（1） 表征唾液中的口腔微生物群并研究其与 HPV 状态和 HPV 基因型的关系， (2) 确定炎性体蛋白（NLRP3、AIM2 和 caspase-）水平之间的关联 1、IL-1β和裂解IL-1β）和炎症标志物（IL-1β、IL-6、IL-8、TNF-α、IFN-γ）与口腔HPV感染 和 HPV 基因型。收集唾液样本后，参与者将接受口腔健康评估。 将通过问卷收集社会人口统计学、行为、临床特征和风险因素。 参与者将接受稳定的抑制性 ART 治疗至少 6 个月，以最大程度地减少因以下原因引起的炎症信号： HIV复制活跃。我们将通过对 16S rDNA 基因和 HPV 进行测序来表征口腔微生物群 通过 PCR 确定基因型。炎症体蛋白和炎症标志物将通过蛋白质印迹法进行测量 分别进行多重ELISA。