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)感染者的主要死亡原因 全球各地的个人。大多数感染结核分枝杆菌(Mtb)的艾滋病毒阴性个人是 无症状，并被认为有潜伏的结核病感染(LTBI)，为宿主提供了令人信服的证据 感染的免疫控制。与艾滋病毒混合感染增加了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。抗逆转录病毒治疗(ART)减少 ATB在艾滋病毒感染者中的发病率，仍然是艾滋病毒护理的基石。然而， 经抗逆转录病毒疗法治疗后，艾滋病毒合并感染者的结核病发病率仍比未感染者高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CD4计数。因此，免疫 抗逆转录病毒疗法并未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，这些方案 同时应用异烟肼预防治疗(IPT)和ART在以下方面明显优于单独应用ART 减少LTBI患者中的结核病发病率。然而，同时采用ART和IPT方案 仍然很差，同时抗逆转录病毒治疗和免疫移植的潜在好处的免疫机制还没有 已定义。 我们建议确定血液和肺中残留的结核免疫成分 在恒河猴中，ART后受损的猕猴与同期ART和IPT恢复的猕猴相比 LTBI与猿猴免疫缺陷病毒(SIV)共感染的非人灵长类动物(NHP)气溶胶模型我们 假设与SIV混合感染增加了肺泡巨噬细胞内的结核分枝杆菌负荷，并 进行性损害肺组织中结核分枝杆菌特异性CD4和CD8T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介导的结核分枝杆菌负担的减少， 与ART联合使用，与单独使用ART相比，可增强保护性结核分枝杆菌特异性T细胞免疫。我们会做模特 在高度可靠的恒河猴结核分枝杆菌/艾滋病毒混合感染模型中，这些并行方案研究 纵向采血、支气管肺泡灌洗对肺特异性CD4和CD8T细胞应答的动态观察 (BAL)和肺活检组织。在目标1中，我们将研究组织驻留的CD4T细胞在重建 同时应用ART/IPT方案与单独应用ART方案后的结核分枝杆菌特异性免疫。在目标2中，我们将检验假设 SIV引起的肺间室结核杆菌特异性CD8功能的进行性损害得到更好的恢复 同时采用ART/IPT方案，而不是单独采用ART。通过确定结核分枝杆菌潜在的修复机制- 同时进行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 转化为免疫途径，可作为宿主导向的结核病/艾滋病毒合并感染的辅助治疗的靶点 纳入到设计更好的结核病疫苗中。

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.