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.

项目摘要/摘要 一种成功的结核病疫苗必须保护最脆弱的人群，包括那些 感染了艾滋病毒。在艾滋病毒感染者中，结核病占死亡人数的比例很大。连 在抑制性抗逆转录病毒治疗(ART)期间，艾滋病毒感染者仍处于较高的进展性风险。 结核病与未感染艾滋病毒的队列进行比较。关于先前存在的艾滋病毒感染如何影响人们，我们知之甚少 后续结核分枝杆菌(Mtb)感染的结果，这将是疫苗接种的一个巨大障碍 发展。对PAR-16-254的回应，《分枝杆菌诱导HIV感染者免疫的机制》 和未受感染的个体提供创新的结核病疫苗设计“，这项提案将集中在 被抑制或未被抑制的猴免疫缺陷(SIV)感染对结核分枝杆菌感染的影响 猕猴模型中的感染。我们的主要假设是，先前存在的SIV感染将影响 随后感染结核分枝杆菌的结局。当SIV复制符合以下条件时，进展结核病的风险最大 不受抑制，导致免疫反应受损，从而导致高细菌负担和传播。我们 建议进行一系列活体成像和分子技术以追踪单个结核分枝杆菌 单个肉芽肿和其他组织及其与SIV复制、进化和免疫的相关性 回应。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 结核分枝杆菌感染的发病机制以及随后的结核分枝杆菌感染如何改变SIV复制和多样性 感染。在目标2中，我们将描述在这两个过程中的先天和获得性免疫反应。 感染以及SIV诱导的免疫激活因子以确定存在的免疫缺陷 抑制或不抑制SIV和结核分枝杆菌联合感染。最后，在目标3中，我们将关联SIV的动力学 随着时间的推移，肉芽肿和其他组织中的复制、结核杆菌的生长和传播以及免疫 检查结核分枝杆菌感染(细菌生长、杀死和传播)和SIV病毒复制和 肉芽肿和其他感染部位免疫反应的演变。通过比较这些 在抑制和非抑制SIV感染和SIV非感染组之间的结果，我们将有一个 更好地了解HIV-Mtb联合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患有抑制性或非抑制性的人类 居住在结核病流行地区的艾滋病毒感染者。这项建议也将为 先前存在的艾滋病毒感染的免疫缺陷对控制结核分枝杆菌感染至关重要。这样的发现将会 在未来保护艾滋病毒感染者的疫苗的战略开发和设计中至关重要 个人对结核病的防治。