Changes in Enteric Microbiota and Inflammation with HIV PrEP

HIV PrEP 引起的肠道微生物群变化和炎症

• 批准号: 10700595
• 负责人: Brandon Swartz Maust
• 金额: $ 19.36万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700595
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Affect; Anti-Inflammatory Agents; Anti-Retroviral Agents; Antibiotics; Area; Award; Bacteria; Bacteriophages; Biometry; Blood; Blood specimen; Career Mobility; Cells; Child; Clostridium difficile; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Computational Biology; Control Groups; DNA; Development; Development Plans; Disease; Enrollment; Enteral; Epithelial Cells; Epithelium; Feces; Fumarates; Functional disorder; Future; Generations; Genes; Goals; Growth; HIV; HIV Infections; Health; Human; Immune; Immune system; Immunity; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Intervention; Intestines; Literature; Measures; Medicine; Metagenomics; Methods; Modeling; Mucositis; Mus; Nucleosides; Nutritional; Organism; Participant; Pathogenicity; Persons; Physicians; Population; Predatory Behavior; Predisposition; Probiotics; Prokaryotic Cells; Prophages; RNA Sequences; Research; Resources; Reverse Transcriptase Inhibitors; Risk Factors; Risk Reduction; Safety; Sampling; Scientist; Series; Shapes; Shotgun Sequencing; Signal Transduction; Specimen; Structure; Techniques; Tenofovir; Testing; Therapeutic Intervention; Training; Ulcerative Colitis; Validation; Viral; Viral Genome; Virion; Virus; Visit; bacterial community; bacteriome; career development; cohort; dysbiosis; emtricitabine; enteric dysbiosis; experimental study; global health; gut inflammation; gut microbiota; improved; inflammatory marker; member; metagenome; metagenomic sequencing; microbial; microbicide; microbiome; microbiota; microorganism interaction; multiple omics; novel; particle; pathobiont; pre-exposure prophylaxis; prebiotics; prevent; response; stool sample; symbiont; systemic inflammatory response; virome; volunteer

PROJECT SUMMARY/ABSTRACT Although HIV remains a major global health problem, strategies such as Pre-Exposure Prophylaxis (PrEP) can reduce the incidence of new infections. However, the antiretrovirals used for HIV prevention have been associated with increased enteric inflammation in individuals using them. We hypothesize that their broad activity affects both the viral and bacterial communities of the gut, causing local inflammation which may cause epithelial dysfunction and increase microbial translocation and systemic inflammation. We propose a series of metagenomic experiments to characterize the inflammatory contributions of intestinal viruses and bacteria and their changes with PrEP. For this novel research, we must first enroll a cohort of participants starting HIV PrEP and a similar group of control participants not using PrEP. We will collect blood and stool samples at baseline and after three months. First, we will characterize the virome fromstool specimens using metagenomic sequencing of filtered viral particles and compare the changes of within- and between- individual diversity in the participants on PrEP and those in the control group (aim 1). Next, we will use metagenomic sequencing to characterize stool bacterial populations, including prophages (aim 2). We will computationally predict bacterial targets of bacteriophages, then culture the identified virus-bacterial pairs from participant specimens. Using these cultures, we will validate the predicted interactions and assess the ability of PrEP to disrupt them. Finally, we will measure inflammatory markers in stool and blood and use the viral and bacterial abundances to identify which organisms are most strongly associated with inflammation (aim 3). These experiments will identify viruses and bacteria which interact with each other and with PrEP and define their impact on host inflammation. Dr. Maust’s career development plan builds on his background in computational biology, and lab expertise in analyzing bacterial communities by marker gene sequencing and adds training in metagenomic sequencing, biostatistical techniques, and methods for viral and bacterial culture. This K08 award is a well-structured way for him to make maximal use of UW and Seattle Children’s extensive scientific resources to achieve independence as a physician scientist, advancing his career goal to understand microbial interactions as they impact host immunity to guide therapeutic interventions.

项目摘要/摘要 尽管艾滋病毒仍然是一个主要的全球健康问题，但诸如暴露前预防（PREP）之类的策略可以 减少新感染的发生率。但是，用于预防HIV的抗逆转录病毒病已是 与增加使用它们的个体的促进炎症有关。我们假设他们的广泛活动 影响肠道的病毒和细菌群落，导致局部炎症，可能导致上皮 功能障碍并增加微生物易位和全身性炎症。 我们提出了一系列的宏基因组实验，以表征肠道的炎症贡献 病毒和细菌及其随着准备的变化。对于这项新研究，我们必须首先注册 参与者开始HIV PREP和类似的对照参与者不使用PREP的参与者。我们会收集血液 和三个月后的粪便样品。首先，我们将表征病毒蛋白源标本 使用过滤的病毒颗粒的宏基因组测序，并比较内部和之间的变化 参与者和对照组的参与者中的个人多样性（AIM 1）。接下来，我们将使用 元基因组测序以表征粪便细菌种群，包括依据（AIM 2）。我们将 计算预测细菌的细菌靶标，然后培养已鉴定的病毒 - 细菌对 参与标本。使用这些培养物，我们将验证预测的相互作用并评估 准备破坏它们。最后，我们将测量粪便和血液中的炎症标记，并使用病毒和 细菌丰度以识别哪些生物与炎症最密切相关（AIM 3）。这些 实验将鉴定病毒和细菌相互相互作用并与PREP相互作用并定义其 对宿主炎症的影响。 Maust博士的职业发展计划以其计算生物学背景为基础，实验室专业知识 通过标记基因测序分析了细菌群落，并增加了宏基因组测序的训练， 生物统计技术以及病毒和细菌培养的方法。这个K08奖是一种结构良好的方式 他将最大程度地利用西澳大学和西雅图儿童的广泛科学资源来实现独立性 作为一名物理科学家，促进他的职业目标，以了解微生物互动，因为它们会影响主机 免疫以指导治疗干预措施。