The role of penile bacteria and inflammation in HIV susceptibility; Rakai, Uganda

阴茎细菌和炎症在艾滋病毒易感性中的作用；

• 批准号: 9478083
• 负责人: Lance Bradley Price
• 金额: $ 63.44万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9478083
• 关键词: AIDS prevention; Address; Age; Anaerobic Bacteria; Bacteria; Bacteriophages; Behavioral; Biological; Biological Response Modifiers; CCL2 gene; CD4 Positive T Lymphocytes; Cell Density; Cells; Classification; Coitus; Custom; Data; Development; Enrollment; Epithelium; Excision; Flow Cytometry; Genital system; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV Seropositivity; HIV risk; Heterosexuals; Human Herpesvirus 2; Human Papillomavirus; IL8 gene; Immune; Immune response; Immunohistochemistry; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-17; Knowledge; Lead; Link; Male Circumcision; Measures; Molecular; Mucositis; Nested Case-Control Study; Odds Ratio; Operative Surgical Procedures; Phylogenetic Analysis; Population; Predisposition; Prevention strategy; Production; Randomized Controlled Trials; Research Design; Risk; Role; Sampling; Serologic tests; Sex Behavior; Swab; Taxonomy; Testing; Time; Tissues; Uganda; Urethra; Virus; Visit; Work; Wound Healing; antimicrobial; arm; bacteriocin; base; cytokine; density; epidemiologic data; epidemiology study; follow-up; improved; innovation; men; novel; novel strategies; penile microbiome; penile microbiota; penis foreskin; prevent; prospective; rRNA Genes; recruit; seroconversion

PROJECT SUMMARY Penile anaerobes are significantly reduced after male circumcision (MC), but it is unclear if these anaerobes cause genital inflammation and increase HIV susceptibility. Without this knowledge, we are unlikely to understand the role of the penile microbiome in mucosal inflammation and HIV susceptibility. Our long-term goal is to develop novel preventative strategies to augment MC. This project's objective, which is the logical next step toward our goal, is to determine the impact of penile anaerobes on HIV risk. Our central hypothesis is that penile anaerobes increase HIV susceptibility in men, irrespective of MC status, and that penile anaerobes can both stimulate local synthesis of innate immune mediators and increase recruitment and activation of HIV- susceptible cells in the penile epithelium. Our rationale for this work is that, once we know how penile anaerobes influence genital inflammation and HIV risk, we could develop novel strategies, such as narrow- spectrum antimicrobials (e.g., bacteriocins, bacteriophages) to reduce penile anaerobe load or genital inflammation. We will achieve our objectives by accomplishing the following specific aims: Aim 1: Determine the association between penile anaerobes and HIV acquisition in men using samples and epidemiologic data from the Rakai MC trial. We will directly assess whether penile anaerobes are associated with increased HIV risk, using a nested case-control study design and existing samples from seroconverters (prior to seroconversion) (n = 93) and seronegative controls from the Rakai MC Randomized- controlled trial (RCT), matched at 1:2. Aim 2: Determine the correlation between penile anaerobes and HIV target cell recruitment and activation. We will enroll 194 HIV-negative men, ages 15-49, who request MC. We will collect urethral and coronal sulcus swabs prior to MC and foreskin tissue at time of MC to analyze the penile microbiome and foreskin HIV target cell activation and density. Aim 3: Define the temporal association between penile anaerobes and local immune responses. We will sample 104 men, ages 15-49, over an 8-month period, including 52 men from Aim 2 and an additional 52 HIV-negative men who decline MC. We will begin sampling circumcised men after complete wound healing at 6 weeks post-MC. Using these longitudinal coronal sulcus swabs, we will determine penile microbiome stability and the temporal association between anaerobe and inflammatory cytokine production. The approach is innovative, in this team's opinion; because it will identify penile anaerobe strains associated with HIV seroconversion and the most potent inducers of mucosal inflammation, irrespective of MC status. The project is significant because it will elucidate role of penile microbiome in HIV acquisition and has the potential to lead to new non-surgical options for men who decline MC and novel strategies to augment MC.

项目摘要 男性包皮环切术（MC）后阴茎厌氧菌明显减少，但尚不清楚这些厌氧菌是否 导致生殖器炎症并增加艾滋病毒易感性。如果没有这些知识，我们不太可能 了解阴茎微生物组在粘膜炎症和HIV易感性中的作用。我们的长期 我们的目标是开发新的预防策略来增加MC。这个项目的目标，这是合乎逻辑的 我们的下一步目标是确定阴茎厌氧菌对艾滋病风险的影响。我们的核心假设是 阴茎厌氧菌增加了男性对HIV易感性，与MC状态无关， 既能刺激先天免疫介质的局部合成，又能增加HIV的募集和激活， 阴茎上皮中的易感细胞。我们这项工作的理由是，一旦我们知道阴茎如何 厌氧菌影响生殖器炎症和艾滋病毒的风险，我们可以开发新的策略，如窄- 光谱抗菌剂（例如，细菌素，噬菌体），以减少阴茎厌氧菌负荷或生殖器 炎症我们将通过实现以下具体目标来实现我们的目标： 目的1：确定男性阴茎厌氧菌与HIV感染之间的关系， Rakai MC试验的样本和流行病学数据。我们将直接评估阴茎厌氧菌 与HIV风险增加相关，使用巢式病例对照研究设计和来自 血清转换者（血清转换前）（n = 93）和来自Rakai MC的血清阴性对照 对照试验（RCT），1：2匹配。 目的2：确定阴茎厌氧菌与HIV靶细胞募集的相关性， activation.我们将招募194名HIV阴性男性，年龄15-49岁，要求MC。我们将收集尿道和 MC前的冠状沟拭子和MC时的包皮组织，以分析阴茎微生物组， 包皮HIV靶细胞的活化和密度。 目的3：确定阴茎厌氧菌和局部免疫反应之间的时间关联。 我们将在8个月的时间内对104名年龄在15-49岁之间的男性进行抽样，其中包括来自Aim 2的52名男性和另外一名男性。 52例HIV阴性男性，MC下降。我们将在伤口完全愈合后开始对包皮环切的男性进行取样 在MC后6周。使用这些纵向冠状沟拭子，我们将确定阴茎微生物组 稳定性以及厌氧菌和炎性细胞因子产生之间的时间关联。 在这个团队看来，这种方法是创新的，因为它将识别阴茎厌氧菌菌株 与HIV血清转换和粘膜炎症的最有效诱导剂相关，无论MC status.该项目意义重大，因为它将阐明阴茎微生物组在艾滋病毒感染中的作用， 为MC下降的男性提供新的非手术选择和增加MC的新策略的潜力。