Genital Anaerobes, Inflammation and HIV Risk; Rakai

生殖器厌氧菌、炎症和艾滋病毒风险；

• 批准号: 8290473
• 负责人: RONALD H GRAY
• 金额: $ 72.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290473
• 关键词: AIDS prevention; Address; Affect; Age; Alcohol consumption; Anaerobic Bacteria; Antibiotics; Bacteria; Bacterial Vaginosis; Base Ratios; Behavioral; Biological Assay; Blood; Budgets; Buffers; CCL2 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXC chemokine IP-10; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cell Density; Chemotactic Factors; Chlamydia; Collaborations; Communities; Consent; Couples; Data; Dendritic Cells; Dermis; Detection; Development; Disease; Enrollment; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemiologist; Epidemiology; Epidermis; Exposure to; Family; Female; Future; Genes; Genital system; Gonorrhea; Gray unit of radiation dose; HIV; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV vaccine; Histologic; Human Herpesvirus 2; Human Papillomavirus; IL8 gene; Image Analysis; Immune; Immunologist; Immunology; Incidence; Individual; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Interferons; Interleukin-10; Interleukin-12; Interleukin-6; Interleukins; Intervention; Laboratories; Langerhans cell; Link; Logistic Regressions; Male Circumcision; Maryland; Measurement; Measures; Mediating; Mediation; Methods; Modeling; Molecular; Monokines; Mucositis; Mucous Membrane; Mycoplasma genitalium; Odds Ratio; Operative Surgical Procedures; Organism; Participant; Persons; Play; Population; Population Attributable Risks; Postoperative Period; Predisposition; Prevention Research; Prevention strategy; Price; Prostitution; Proteins; RANTES; Randomized; Relative (related person); Research; Research Personnel; Ribosomal RNA; Risk; Risk Factors; Role; Sampling; Sexual Partners; Sexually Transmitted Diseases; Spearman Rank Correlation Coefficient; Swab; Symptoms; Syphilis; System; T-Lymphocyte; TNF gene; Testing; Time; Tissues; Topical Antibiotic; Translating; Trichomonas vaginalis; Tumor Necrosis Factor-alpha; Uganda; Ulcer; Universities; Vagina; Viral Load result; Visit; Woman; arm; base; chemokine; cofactor; condoms; control trial; cytokine; design; editorial; epidemiologic data; experience; follow-up; hazard; high risk; indexing; inflammatory marker; insight; interest; macrophage; male; men; microbicide; novel; novel strategies; pathogen; penis foreskin; phase 1 study; public health relevance; rRNA Genes; randomized trial; response; sex; sex risk; topical antiseptic; transmission process

DESCRIPTION (provided by applicant): "Classical" sexually transmitted infections (STIs) and bacterial vaginosis (BV) are associated with HIV susceptibility and infectivity. However, trials of STI control for HIV prevention have been largely negative. We hypothesize that other genital organisms may induce inflammation and contribute to increased risk of HIV. We will use data and samples collected during a trial of male circumcision (MC) to assess this hypothesis. HIV-negative men were randomized to immediate MC (intervention) or MC delayed by 2 years (controls). Men provided blood and penile swabs at 0, 6, 12 and 24 months. Foreskins were preserved at time of MC. Female partners of these men provided blood and vaginal swabs at 0, 12 and 24 months. Using these materials, we will address the following aims: Aim1. 1a) Assess the correlation between the genital burden of anaerobes and levels of genital cytokines/chemokines in 100 intervention and 100 control men and their 200 female partners.1.b) Assess the association between these exposures and histologic inflammation in foreskin tissues. 1.c. Using the data from Aim 1.a, we will assess the effects of MC on genital anaerobes and inflammatory markers in intervention versus control arm men and their partners. Aim 2. Assess the burden of genital anaerobes and levels of cytokines/chemokines associated with HIV acquisition using a case-control analysis of 105 male and 89 female HIV seroconverters, and 388 HIV-uninfected controls. Adjusted odds ratios will be estimated by multivariable logistic regression. Aim 3. In 310 HIV discordant couples we will estimate rates of HIV transmission/acquisition associated with genital anaerobe burden and cytokine/ chemokine levels. Incidence rate ratios of HIV acquisition/transmission will be estimated by Poisson multivariable regression. In an additional Aim 4, we will utilize the data from Aims 1-3 to assess the mediating role of anaerobes and inflammation on MC efficacy for HIV prevention in men. Laboratory methods: Total bacterial load, and the relative and absolute anaerobe burdens will be assessed by16S rRNA qPCR and 16SrRNA gene-based pyrosequencing. Cytokine and chemokine concentrations will be assayed using multiplex sandwich ELISA (SearchLight, Aushon Biosystems, MA) for TNFa, IFN?, IL-1¿, IL-8, IL-6, IL-12, RANTES, Monokine Induced by IFN? (MIG/CXCL9), Macrophage Chemotactic Protein (MCP1/CCL2), and Interferon Inducible Protein-10 (IP10/CXCL10). This is a multidisciplinary collaboration between epidemiologists, molecular biologists and immunologists, and includes a new investigator (Dr. L Price, co-PI). PUBLIC HEALTH RELEVANCE: If genital anaerobes cause mucosal inflammation and are associated with HIV acquisition/transmission, the study could facilitate development of novel approaches to HIV prevention by control of pro-inflammatory genital anaerobes (e.g., by use of topical antiseptics or antibiotics), or agents to modulate genital inflammatory responses in men and women. This could inform microbicide development. Insights into mucosal immunology may also contribute to development of future mucosal HIV vaccines.

描述(申请人提供)：“典型”性传播感染(STI)和细菌性阴道病(BV)与艾滋病毒易感性和传染性有关。然而，用于预防艾滋病毒的性传播感染控制试验在很大程度上是负面的。我们推测，其他生殖器生物可能会引发炎症，从而增加感染艾滋病毒的风险。我们将使用在男性包皮环切术(MC)试验期间收集的数据和样本来评估这一假设。HIV阴性的男性被随机分为即刻MC组(干预组)或延迟2年的MC组(对照组)。男性在0、6、12和24个月时提供血液和阴茎拭子。MC时保留包皮。这些男性的女性伴侣在0、12和24个月时提供了血液和阴道拭子。利用这些材料，我们将实现以下目标：目标1。1a)评估100名干预者和100名对照男性及其200名女性伴侣的生殖器厌氧菌负荷与生殖器细胞因子/趋化因子水平之间的相关性。1)评估这些暴露与包皮组织组织炎症之间的关系。1.C.使用来自Aim 1.A的数据，我们将评估MC在干预中对生殖器厌氧菌和炎症标志物的影响，并与对照组男性及其伴侣进行比较。目的2.通过对105名男性和89名女性HIV血清转换者和388名未感染HIV的对照组进行病例对照分析，评估生殖器厌氧菌的负担和与HIV感染相关的细胞因子/趋化因子水平。调整后的优势比将通过多变量Logistic回归进行估计。目的3.在310对HIV不和夫妇中，我们将估计与生殖器厌氧菌负荷和细胞因子/趋化因子水平相关的HIV传播/获得率。艾滋病毒感染/传播的发病率比率将通过泊松多变量回归进行估计。在另一个目标4中，我们将利用来自目标1-3的数据来评估厌氧菌和炎症在男性预防艾滋病毒的MC疗效中的中介作用。实验室方法：用16S rRNA定量聚合酶链式反应和基于16SrRNA基因的焦磷酸测序法测定细菌总负荷、相对和绝对厌氧菌负荷。细胞因子和趋化因子的浓度将采用多重夹心ELISA法(Searchlight，Aushon BiosSystems，MA)进行检测，以检测由干扰素？诱导的细胞因子和趋化因子的水平。(MiG/CXCL9)、巨噬细胞趋化蛋白(MCP1/CCL2)和干扰素诱导蛋白-10(IP10/CXCL10)。 这是流行病学家、分子生物学家和免疫学家之间的多学科合作，其中包括一名新的研究员(联席研究员L·普赖斯博士)。 公共卫生相关性：如果生殖器厌氧菌引起粘膜炎症并与艾滋病毒感染/传播有关，这项研究可以通过控制促炎生殖器厌氧菌(例如，使用局部消毒剂或抗生素)或调节男性和女性生殖器炎症反应的药物，促进开发预防艾滋病毒的新方法。这可能会为杀微生物剂的开发提供信息。对粘膜免疫学的洞察也可能有助于未来粘膜艾滋病毒疫苗的开发。

项目成果

The semen microbiome and its relationship with local immunology and viral load in HIV infection.

• DOI: 10.1371/journal.ppat.1004262
• 发表时间: 2014-07
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Liu CM;Osborne BJ;Hungate BA;Shahabi K;Huibner S;Lester R;Dwan MG;Kovacs C;Contente-Cuomo TL;Benko E;Aziz M;Price LB;Kaul R
• 通讯作者: Kaul R

Genital Anaerobic Bacterial Overgrowth and the PrePex Male Circumcision Device, Rakai, Uganda.

生殖器厌氧细菌过度生长和 PrePex 男性包皮环切装置，乌干达拉凯。

• DOI: 10.1093/infdis/jiw182
• 发表时间: 2016
• 期刊: The Journal of infectious diseases
• 作者: Liu,CindyM;Prodger,JessicaL;Tobian,AaronAR;Serwadda,David;Galiwango,RonaldM;Nalugoda,Fred;Kighoma,Nehemiah;Mwinike,Joshua;Anyokorit,Margaret;Price,LanceB;Wawer,MariaJ;Kigozi,Godfrey;Gray,RonaldH
• 通讯作者: Gray,RonaldH

Ockham's Razor and the PrePex Male Circumcision Device.

奥卡姆剃刀和 PrePex 男性包皮环切装置。

• DOI: 10.1093/infdis/jiw277
• 发表时间: 2016
• 期刊: The Journal of infectious diseases
• 作者: Liu,CindyM;Tobian,AaronAR;Gray,RonaldH
• 通讯作者: Gray,RonaldH

FungiQuant: a broad-coverage fungal quantitative real-time PCR assay.

• DOI: 10.1186/1471-2180-12-255
• 发表时间: 2012-11-08
• 期刊: BMC microbiology
• 影响因子: 4.2
• 作者: Liu CM;Kachur S;Dwan MG;Abraham AG;Aziz M;Hsueh PR;Huang YT;Busch JD;Lamit LJ;Gehring CA;Keim P;Price LB
• 通讯作者: Price LB

BactQuant: an enhanced broad-coverage bacterial quantitative real-time PCR assay.

• DOI: 10.1186/1471-2180-12-56
• 发表时间: 2012-04-17
• 期刊: BMC microbiology
• 影响因子: 4.2
• 作者: Liu CM;Aziz M;Kachur S;Hsueh PR;Huang YT;Keim P;Price LB
• 通讯作者: Price LB