Impact of concurrent HIV and latent TB therapies on Mtb-specific immune function-Diversity Supplement

摘要 结核病（TB）是人类免疫缺陷病毒（HIV）感染者死亡的主要原因。 全球个人。大多数感染结核分枝杆菌（Mtb）的HIV阴性个体是 无症状，并被认为有潜伏性结核感染（LTBI），提供了令人信服的证据，主机 免疫控制感染。合并感染艾滋病毒会增加进展为活动性结核病（ATB）的风险 超过20倍，但潜在的免疫机制仍不清楚。抗逆转录病毒疗法（ART）减少 艾滋病毒感染者中ATB的发病率，仍然是艾滋病毒护理的基石。但 艾滋病毒合并感染者在接受抗逆转录病毒治疗后的结核病发病率仍比未感染艾滋病毒者高4至7倍 在结核病流行环境中，无论抗逆转录病毒治疗的持续时间或达到高CD 4计数。因此，免疫 抗逆转录病毒疗法不能完全恢复对结核分枝杆菌感染的控制。最近的临床试验表明， 同时给予异烟肼预防性治疗（IPT）和ART明显优于单独使用ART， 降低LTBI患者的结核病发病率。然而，同时接受ART和IPT方案， 仍然很差，同时进行ART和IPT的免疫机制还没有得到证实。 定义了 我们建议确定血液和肺隔室中残留的结核免疫成分， 在恒河猴中，ART后受损，与同时ART和IPT恢复的受损相比， LTBI和猿猴免疫缺陷病毒（SIV）共感染的非人灵长类（NHP）气溶胶模型。我们 假设与SIV共感染增加了肺中肺泡巨噬细胞内的Mtb负荷， 逐渐损害肺中组织驻留的Mtb特异性CD 4和CD 8 T细胞的功能能力; ART只能部分恢复这些功能。我们进一步假设IPT介导的Mtb负担的减少， 与ART联合，与单独ART相比，增强了保护性Mtb特异性T细胞免疫。我们将模型 在恒河猴中的Mtb/HIV共感染的高度忠实模型中，这些并行方案研究了 通过血液纵向采样、支气管肺泡灌洗，肺特异性CD 4和CD 8 T细胞应答的动力学 (BAL)和肺活检组织。在目的1中，我们将研究组织驻留的CD 4 T细胞在重建细胞中的作用。 ART/IPT联合治疗方案与单独ART治疗后的结核分枝杆菌特异性免疫力。在目标2中，我们将检验假设 SIV诱导的肺隔室中Mtb特异性CD 8功能的进行性损害得到更好的恢复， 联合ART/IPT方案的疗效优于单独ART。通过确定结核分枝杆菌恢复的潜在机制， 同时ART和IPT后的特异性免疫功能，我们的研究有可能提供新的见解 进入免疫途径，可作为结核病/艾滋病病毒合并感染的宿主定向免疫疗法的靶点， 设计更好的结核病疫苗。

Abstract Tuberculosis (TB) is the leading cause of death in Human Immunodeficiency Virus (HIV)-infected individuals globally. The majority of HIV-negative individuals infected with Mycobacterium tuberculosis (Mtb) are asymptomatic, and are considered to have latent TB infection (LTBI), providing compelling evidence for host immune control of infection. Co-infection with HIV increases the risk of progressing to active TB disease (ATB) by over 20 fold but the underlying immune mechanisms remain unclear. Antiretroviral therapy (ART) decreases the incidence of ATB in HIV-infected individuals and remains the cornerstone of HIV care. However, the incidence of TB in HIV-coinfected individuals remains 4- to 7-fold higher after ART than in HIV-uninfected people in TB-endemic settings, regardless of the duration of ART or attainment of high CD4 counts. Thus, immune control of Mtb infection is not fully restored by ART. Recent clinical trials have shown that regimens that concurrently administer Isoniazid Preventive Treatment (IPT) and ART are significantly better than ART alone in reducing TB incidence among individuals with LTBI. However, uptake of concurrent ART and IPT regimens remains poor and the immune mechanisms underlying the benefits of concurrent ART and IPT have not been defined. We propose to identify the components of TB immunity in the blood and lung compartments that remain impaired after ART, versus those that are restored by concurrent ART and IPT, in the rhesus macaque nonhuman primate (NHP) aerosol model of LTBI and Simian Immunodeficiency Virus (SIV) co-infection. We hypothesize that coinfection with SIV increases Mtb burden within alveolar macrophages in the lung and progressively impairs the functional capacities of tissue-resident Mtb-specific CD4 and CD8 T cells in the lung; ART only partially restores these functions. We further hypothesize that IPT-mediated reduction in Mtb burden, in conjunction with ART, enhances protective Mtb-specific T cell immunity compared to ART alone. We will model these concurrent regimens in a highly faithful model of Mtb/HIV co-infection in rhesus macaques to study the kinetics of lung-specific CD4 and CD8 T cell responses by longitudinal sampling of blood, bronchoalveolar lavage (BAL) and lung biopsy tissue. In Aim 1 we will investigate the role of tissue-resident CD4 T cells in reconstituting Mtb-specific immunity after concurrent ART/IPT regimens versus ART alone. In Aim 2 we will test the hypothesis that SIV-induced progressive impairment of Mtb-specific CD8 functions in lung compartments are better restored by concurrent ART/IPT regimens than by ART alone. By identifying mechanisms underlying restoration of Mtb- specific immune function after concurrent ART and IPT, our studies have the potential to provide new insights into immune pathways that can be targeted for host-directed adjunctive therapies for TB/HIV co-infection and incorporated into designing better vaccines for TB.