Influence of SIV replication on TB progression and immunity

项目总结/摘要 成功的结核病疫苗必须保护最脆弱的人群，包括那些 艾滋病病毒感染。在艾滋病毒感染者中，结核病造成的死亡人数不成比例。甚至 在抑制性抗逆转录病毒治疗（ART）期间，HIV感染者仍有较高的进展性 结核病与无艾滋病毒感染的队列相比。关于预先存在的艾滋病毒感染如何影响 后续M.结核病（Mtb）感染，这将是疫苗开发的一个巨大障碍， 发展针对PAR-16 - 254，"HIV感染者中分枝杆菌诱导免疫的机制"， 和未受感染的个人，以告知创新的结核病疫苗设计"，这一建议将侧重于 表征抑制或未抑制的猿免疫缺陷（SIV）感染对Mtb的影响 猕猴模型中的感染。我们的总体假设是，预先存在的SIV感染将影响 Mtb感染的后果。当SIV复制为 未被抑制，导致免疫应答受损，从而导致高细菌负荷和传播。我们 我建议进行一系列的体内成像和分子技术，以跟踪个别结核杆菌内 单个肉芽肿和其他组织，并将它们与SIV复制和进化以及免疫 应答在目标1中，我们将评估预先存在的未抑制或抑制的SIV感染如何改变 Mtb感染的发病机制以及随后的Mtb感染如何改变SIV复制和多样性， 感染在目标2中，我们将描述先天性和适应性免疫反应在两个过程中的特点。 感染以及SIV诱导的免疫激活因子，以确定存在于 抑制或未抑制的SIV和Mtb共感染。最后，在目标3中，我们将把SIV的动力学 随着时间的推移，肉芽肿和其他组织内的Mtb复制、生长和传播以及免疫力， 检查结核分枝杆菌感染（细菌生长、杀灭和传播）和SIV病毒复制的影响， 在肉芽肿和其他感染部位的免疫反应背景下的进化。通过比较这些 抑制和未抑制SIV感染和SIV未感染组之间的结果，我们将有一个 更好地了解艾滋病毒-结核病合并感染期间风险的免疫学和病原学特征， 感染这些研究的结果应该直接转化为人类无论是抑制或非抑制 居住在结核病流行区的艾滋病病毒感染者。这一建议也将提供重要的见解， 免疫缺陷的预先存在的艾滋病毒感染，这是至关重要的控制结核分枝杆菌感染。这些发现将 在未来疫苗的战略开发和设计中至关重要， 个人对结核病。

Project Summary/Abstract A successful vaccine against tuberculosis (TB) must protect the most vulnerable populations, including those with HIV infection. TB accounts for a disproportionate number of deaths among HIV-infected individuals. Even during suppressive antiretroviral therapy (ART), HIV-infected individuals remain at higher risk of progressive TB compared to cohorts without HIV infection. Little is known about how pre-existing HIV infection influences the outcome of subsequent M. tuberculosis (Mtb) infection, which will be a formidable obstacle in vaccine development. In response to PAR-16-254, “Mechanisms of mycobacterial-induced immunity in HIV-infected and uninfected individuals to inform innovative tuberculosis vaccine design”, this proposal will focus on characterizing the influence of suppressed or unsuppressed simian immunodeficiency (SIV) infection on Mtb infection in a macaque model. Our overarching hypothesis is that pre-existing SIV infection will affect the outcome of subsequent Mtb infection. The risk of progressive TB is greatest when SIV replication is unsuppressed, resulting in impaired immune responses and, thus, high bacteria burden and dissemination. We propose to perform serial in vivo imaging and molecular techniques to track individual Mtb bacilli within individual granulomas and other tissues and correlating them with SIV replication and evolution and immune responses. In Aim 1, we will assess both how pre-existing unsuppressed or suppressed SIV infection alters the pathogenesis of Mtb infection and how subsequent Mtb infection alters SIV replication and diversity during co- infection. In Aim 2, we will characterize the innate and adaptive immune responses during the course of both infections as well as SIV induced immune activation factors to identify the immunologic deficits present in suppressed or unsuppressed SIV and Mtb co-infection. Lastly, in Aim 3, we will correlate the dynamics of SIV replication, Mtb growth and dissemination, and immunity within granulomas and other tissues over time and examine the effects of Mtb infection (bacterial growth, killing and dissemination) and SIV viral replication and evolution in the context of immune responses in granulomas and other infection sites. By comparing these outcomes between suppressed and unsuppressed SIV infection and SIV uninfected groups, we will have a better fundamental understanding of the immunologic and pathogenic features of risk during HIV-Mtb co- infection. Results of these studies should directly translate to humans with either suppressed or unsuppressed HIV infection who live in TB endemic areas. This proposal will also provide important insights to the immunologic deficits in pre-existing HIV infection that are critical to controlling Mtb infection. Such findings will be essential in the strategic development and design of future vaccine vaccines that will protect HIV-infected individuals against TB.