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: 8116974
• 负责人: MICHAEL A POLES
• 金额: $ 26.85万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8116974
• 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; 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.

保护性免疫需要在获得的和先天免疫系统之间相互作用。 尽管已经取得了巨大的进步，以理解被收购的关键作用 免疫系统在防御艾滋病毒感染的防御中，我们对先天免疫作用的了解 相当有限。 GL粘膜免疫系统在防止感染中起着至关重要的作用 艾滋病毒和机会性病原体，部分通过粘膜分泌物，其中包含丰富的种类 可溶性先天免疫介质。我们假设1）在易感性中发现的差异 艾滋病毒（口腔与直肠和阴道）的粘膜感染是由于类型差异而引起的 分泌物中的可溶性先天免疫介体的浓度，2）风险增加 通过免疫选择的GL机会感染的发展是导致下降的结果 粘膜对先天免疫介质的分泌，3）免疫抑制也是相关的 随着粘膜微生物群的批发变化，4）局部微生物群的改变有助于 改变先天免疫的可溶性介体的分泌，4）增加了粘膜 促炎细菌种类的定殖将导致刺激的介体分泌 粘膜HIV复制。因此，我们建议1）检验HIV NFECTION的假设 与可溶性先天免疫介质的抑郁粘膜分泌有关，2）测试 假设艾滋病毒通过对先天免疫的分泌的影响，艾滋病毒引起的免疫选择 蛋白质，导致粘膜微生物群多样性的变化在几种GL粘膜中 站点，3）检验以下假设：粘膜微生物群改变的改变 免疫介质，这反过来影响GL粘膜中的HIV复制。知识获得了 从拟议的研究中可能导致抑制艾滋病毒复制的机制，改变自然 艾滋病毒疾病的病史并降低了粘膜部位对艾滋病毒感染的敏感性。