Effect of HIV Infection on Soluble Mediators and Microbial Biota in the GI Tract

HIV 感染对胃肠道可溶性介质和微生物群的影响

• 批准号: 7291227
• 负责人: MICHAEL A POLES
• 金额: $ 26.82万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291227
• 关键词: Adjuvant; Affect; Anatomic Sites; Bacteria; Biological Response Modifiers; Biopsy; Biota; CD4 Positive T Lymphocytes; Collaborations; Defensins; Depressed mood; Development; Disease; Distal; Duodenum; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Esophageal; Esophagus; Gastrointestinal tract structure; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Host Defense; Immune; Immune system; Immunity; Immunohistochemistry; Immunologics; Immunosuppression; In Situ; In Vitro; Infection; Knowledge; Lactoferrin; Lead; Leukocytes; Macrophage Inflammatory Protein-1; Mediator of activation protein; Messenger RNA; Modeling; Mucous Membrane; Muramidase; Natural History; Natural Immunity; Opportunistic Infections; Oral; Oral cavity; Pattern; Play; Population; Predisposition; Protease Inhibitor; Proteins; Proteomics; Reflux; Resistance; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Route; Secretory Immunoglobulin A; Simple Columnar Epithelium; Site; Small Intestines; Source; Stomach; Surface; T-Cell Depletion; T-Lymphocyte; Techniques; Testing; Therapeutic immunosuppression; Vagina; acquired immunity; chemokine; gastrointestinal; improved; insight; interest; microbial; mucosal site; novel; oral HIV; pathogen; reconstitution; rectal; research study; response

Protective immunity requires interaction between the acquired and the innate immune systems. While great advances have been made towards understanding the critical role of the acquired immune system in the defense against HIV infection, our knowledge of the role of innate immunity is rather limited. The Gl mucosal immune system plays a vital role in protection against infection by HIV and opportunistic pathogens, in part through mucosal secretions, containing a rich variety of soluble innate immune mediators. We hypothesize 1) that differences identified in the susceptibility of mucosal infection by HIV (oral vs. rectal and vaginal) are a result of differences in the types and concentrations of soluble innate immune mediators in their secretions, 2) that the increased risk of development of Gl opportunistic infections with immunosupression are a result of decreased secretion of innate immune mediators by the mucosa, 3) that immunosuppression is also associated with wholesale changes in the mucosal microbiota, 4) that alterations in the local microbiota contribute to alteration in the secretion of soluble mediators of innate immunity, and 4) that increased mucosal colonization by proinflammatory bacterial species will result in secretion of mediators that stimulate mucosal HIV replication. We therefore propose to 1) to test the hypothesis that HIV nfection is associated with depressed mucosal secretion of soluble innate immune mediators, 2) to test the hypothesis that HIV-induced immunosupression, through its effects on secretion of innate immune proteins, results in changes in the diversity of the mucosal microbiota throughout several Gl mucosal sites, and 3) to test the hypothesis that alterations of the mucosal microbiota alter secretion of immune mediators, which in turn affect HIV replication in the Gl mucosa. The knowledge gained from the proposed studies may lead to mechanisms to suppress HIV replication, alter the natural history of HIV disease and decrease the susceptibility of mucosal sites to HIV infection.

保护性免疫需要获得性免疫系统和先天免疫系统之间的相互作用。 尽管在理解所获得的关键作用方面已经取得了巨大进展 免疫系统在防御艾滋病毒感染中，我们对先天免疫作用的了解 是相当有限的。胃肠道粘膜免疫系统在预防感染方面发挥着至关重要的作用 HIV和机会性病原体，部分通过粘膜分泌物，含有丰富的多种 可溶性先天免疫介质。我们假设 1) 易感性存在差异 HIV 粘膜感染（口腔与直肠和阴道）的差异是由于类型和 其分泌物中可溶性先天免疫介质的浓度，2) 增加的风险 免疫抑制导致胃肠道机会性感染的发生是由于免疫抑制减少的结果 粘膜分泌先天免疫介质，3) 免疫抑制也与之相关 随着粘膜微生物群的大规模变化，4) 局部微生物群的改变有助于 改变先天免疫的可溶性介质的分泌，4) 增加粘膜 促炎细菌的定植将导致分泌刺激介质 粘膜HIV复制。因此，我们建议 1) 检验 HIV 感染是 与可溶性先天免疫介质的粘膜分泌抑制相关，2) 测试 假设艾滋病毒通过其对先天免疫分泌的影响而诱导免疫抑制 蛋白质，导致整个胃肠道粘膜微生物群多样性的变化 位点，以及 3) 检验粘膜微生物群的改变会改变分泌的假设 免疫介质，进而影响HIV在胃肠道粘膜中的复制。获得的知识 拟议的研究可能会产生抑制艾滋病毒复制、改变自然状态的机制。 HIV病史并降低粘膜部位对HIV感染的易感性。