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

保护性免疫需要后天免疫系统和先天免疫系统之间的相互作用。 虽然在理解获得者的关键作用方面已经取得了很大进展 免疫系统在防御HIV感染中的作用，我们对先天免疫的认识 是相当有限的。Gl粘膜免疫系统在预防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，含有丰富的种类 可溶性的先天免疫介体。我们假设1)在敏感度上发现的差异 HIV粘膜感染(口腔与直肠和阴道)的不同是由于类型和 分泌物中可溶性天然免疫介质的浓度，2)增加的风险 发生Gl机会性感染并免疫抑制的原因是 粘膜分泌天然免疫介质，3)免疫抑制也与此有关 随着黏膜微生物区系的大规模变化，4)当地微生物区系的变化有助于 与先天免疫可溶性介质分泌的改变有关，以及4)增加粘膜 致炎细菌的定植将导致刺激刺激的介质的分泌 粘膜内HIV复制。因此，我们建议1)检验艾滋病毒感染是 与可溶性天然免疫介质的粘膜分泌抑制有关，2)测试 HIV通过影响先天免疫分泌诱导免疫抑制的假说 蛋白质，导致在几个G1粘膜中粘膜微生物区系的多样性的变化 3)检验黏膜微生物区系的改变改变分泌的假设 免疫介质，这反过来影响艾滋病毒在G1粘膜中的复制。所获得的知识 从建议的研究可能导致抑制艾滋病毒复制的机制，改变自然 并降低粘膜部位对艾滋病毒感染的易感性。

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.