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

摘要 结核病是人类免疫缺陷病毒(HIV)感染者的主要死亡原因 全球范围内。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艾滋病毒的人高4至7倍。 处于结核病流行环境中的人，无论接受抗逆转录病毒治疗的时间长短或达到高CD4计数。因此， 抗逆转录病毒疗法不能完全恢复对结核分枝杆菌感染的免疫控制。最近的临床试验表明，这些方案 同时实施异烟肼预防治疗(IPT)和ART明显优于ART 这是唯一能降低腰椎结核患者结核病发病率的方法。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 未定义。 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SIV合并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 在恒河猴中高度忠实的结核分枝杆菌/艾滋病毒混合感染模型中模拟这些同时使用的方案 通过纵向采血研究肺特异性CD4和CD8T细胞应答的动力学 支气管肺泡灌洗(BAL)和肺活检组织。在目标1中，我们将研究组织驻留的作用 CD4T细胞在同时应用ART/IPT方案与单独应用ART方案后重建结核分枝杆菌特异性免疫中的作用在……里面 目的2我们将检验SIV引起结核分枝杆菌特异性CD8功能进行性损害的假设。 同时应用ART/IPT方案比单独应用ART方案更能恢复肺间室。通过识别 ART和IPT同时进行后结核分枝杆菌特异性免疫功能恢复机制的研究 有可能为宿主定向的免疫途径提供新的见解 结核病/艾滋病毒混合感染的辅助疗法，并纳入了更好的结核病疫苗的设计。

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 co-infection 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.