Influence of SIV replication on TB progression and immunity

SIV 复制对结核病进展和免疫的影响

• 批准号: 10172837
• 负责人: Zandrea Ambrose
• 金额: $ 94.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-26 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172837
• 关键词: Address; Affect; Animal Model; Animals; Area; Bacillus; Bacteria; Bar Codes; Blood; CD4 Lymphocyte Count; Cells; Cessation of life; Communicable Diseases; Computational Biology; Data; Defect; Development; Disease; Disease Progression; Evolution; Future; Granuloma; Growth; HIV; HIV Infections; HIV Seronegativity; HIV/TB; Human; Image; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologic Factor Activation; Immunologics; Impairment; Incidence; Individual; Infection; Knowledge; Lead; Macaca; Maps; Measures; Methods; Microbiology; Modeling; Molecular; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathogenicity; Play; Prevention; Public Health; Risk; Role; Severities; Severity of illness; Site; Techniques; Therapeutic; Time; Tissues; Translating; Tuberculosis; Tuberculosis Vaccines; Vaccine Design; Vaccines; Viral; Viral Load result; Viral reservoir; Virus Replication; Vulnerable Populations; adaptive immune response; antiretroviral therapy; co-infection; cohort; deep sequencing; design; high risk; immune activation; improved; improved outcome; in vivo; in vivo imaging; innovation; insight; mortality; mycobacterial; novel; pathogen; response; spatiotemporal; synergism; tool; treatment optimization; vaccination against tuberculosis; vaccine development

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.

项目概要/摘要 成功的结核病疫苗必须保护最脆弱的人群，包括那些 艾滋病毒感染者中，结核病造成的死亡人数不成比例。 在抑制性抗逆转录病毒治疗 (ART) 期间，HIV 感染者仍面临进行性进展的较高风险 与未感染艾滋病毒的人群相比，人们对先前存在的艾滋病毒感染如何影响知之甚少。 随后结核分枝杆菌（Mtb）感染的结果，这将是疫苗研发的一个巨大障碍 针对 PAR-16-254，“HIV 感染者的分枝杆菌诱导免疫机制”。 和未感染的个体为创新的结核病疫苗设计提供信息”，该提案将重点关注 表征抑制或未抑制的猿猴免疫缺陷 (SIV) 感染对 Mtb 的影响 我们的总体假设是，先前存在的 SIV 感染会影响猕猴模型中的感染。 随后 Mtb 感染的结果 当 SIV 复制时，进展性结核病的风险最大。 不受抑制，导致免疫反应受损，从而导致高细菌负担和传播。 执行连续体内成像和分子提议技术来追踪单个 Mtb 杆菌 个体肉芽肿和其他组织，并将它们与 SIV 复制、进化和免疫相关联 在目标 1 中，我们将评估先前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 在目标 2 中，我们将描述感染过程中的先天性和适应性免疫反应。 感染以及 SIV 诱导的免疫激活因子，以确定存在的免疫缺陷 最后，在目标 3 中，我们将关联 SIV 的动态。 随着时间的推移，复制、结核分枝杆菌生长和传播以及肉芽肿和其他组织内的免疫力 检查 Mtb 感染（细菌生长、杀灭和传播）和 SIV 病毒复制的影响 通过比较这些，了解肉芽肿和其他感染部位免疫反应的演变。 抑制和未抑制的 SIV 感染组与未感染 SIV 组之间的结果，我们将得到 更好地了解 HIV-Mtb 共存期间风险的免疫学和致病特征 这些研究的结果应该直接转化为抑制或未抑制感染的人类。 该提案也将为居住在结核病流行地区的艾滋病毒感染者提供重要的见解。 先前存在的艾滋病毒感染的免疫缺陷对于控制结核分枝杆菌感染至关重要。 对于保护艾滋病毒感染者的未来疫苗的战略开发和设计至关重要 个人对抗结核病。