Host factors, inflammation, and HIV associated TB

 描述（由申请人提供）： 虽然结核分枝杆菌（MTb）感染是艾滋病死亡的最大原因，也是全球艾滋病毒相关肺部疾病的主要原因，但对结核病合并感染如何影响长期免疫重建或HIV-1储库知之甚少。柬埔寨抗逆转录病毒药物（ART）早期与晚期引入（CAMELIA）随机临床试验显示，早期开始ART（TB治疗开始后2周与8周时晚期ART） 周），导致CD 4 + T细胞计数<200个细胞/mm 2的TB+/HIV+患者的死亡率显著降低（34%），生存益处持续至少3年。我们在嵌套子研究中检查了CAMELIA随机临床试验中TB+/HIV+个体的T细胞应答的初步数据，表明TB和TB相关免疫重建综合征（TB-IRIS）导致治疗开始后至少8个月T细胞区室发生深刻变化。例如，TB共感染和TB-IRIS与大量T细胞活化（包括升高的CCR 5 + T细胞）相关，并导致对中枢记忆（TCM）（CD 62 L + CD 45 RA-）CD 4 +T细胞（主要外周HIV储库组分和效应记忆）的比例的显著影响。在经历TB-IRIS的患者中，我们观察到与对照TB相关的T效应（TEM）（CD 62 L-CD 45 RA-）CD 4 +T细胞的相互扩增。此外，TB-IRIS患者的CXCR 3 + CCR 6 + CD 4 + T细胞升高，这被认为是介导了大部分的CD 4+抗TB反应，这些CXCR 3 + CCR 6 + CD 4 + T细胞在ART开始后至少8个月内保持显著升高。基于我们的初步数据，我们假设我们在TB-IRIS中观察到的不同细胞反应可能代表了对TB的重要保护性反应。我们假设，在结核病流行环境中，对治愈的前CAMELIA患者和稳定的ART患者的这些反应进行评估，将导致对保护性反应和未来疫苗开发重要的新抗原的鉴定。缺乏TB感染、TB-IRIS和TB/HIV合并感染的宿主生物标志物以及相关的临床结果。使用RNA微阵列，我们将确定与TB合并感染、TB-IRIS和抗原特异性TB反应相关的特征。我们假设，在这一非常充分表征的患者队列中的这种分析将提供TB共感染、TB疾病的遏制和与体外测定相关的保护性应答的稳健和新颖的生物标志物。最后，使用来自CAMELIA的TB+/ HIV+患者或同时开始ART的具有相似基线特征的TB-/HIV+患者的存档PBMC，我们将检验以下假设：TB合并感染和TB-IRIS在ART开始后数月和数年后调节ART开始后的HIV储库嗜性，并且还可能影响储库大小。这些实验的发现对于改善TB/HIV合并感染的治疗和我们对TB/HIV的宿主免疫应答的一般理解以及提供表明TB合并感染可以影响HIV储库的组成的第一个证据将具有重要价值。

 DESCRIPTION (provided by applicant): Although infection with Mycobacterium tuberculosis (MTb) is the largest cause of death in AIDS, and it is the major cause of HIV-associated pulmonary disease globally, little is known about how TB co-infection impacts long term immune reconstitution or the HIV-1 reservoir. The Cambodian Early vs. Late Introduction of Anti- retrovirals (ART) (CAMELIA) randomized clinical trial showed that early initiation of ART (2 weeks after TB therapy initiation versus late ART at 8 weeks), resulted in a significant (34%) decrease in mortality in TB+/HIV+ patients with a CD4+ T cell count <200 cells/mm, a survival benefit that persisted for at least 3 years. Our preliminary data examining T cell responses in TB+/HIV+ individuals from the CAMELIA randomized clinical trial in a nested substudy, demonstrated that TB and TB-associated immune reconstitution syndrome (TB-IRIS) results in profound changes in the T cell compartment for at least 8 months after treatment initiation. For example, TB co-infection and TB-IRIS is associated with massive T cell activation including elevated CCR5+ T cells and results in significant impact on the proportions of central memory (TCM) (CD62L+CD45RA-) CD4+T cells, the major peripheral HIV reservoir component and effector memory. In patients who experienced TB- IRIS, we observed a reciprocal expansion of T effector (TEM) (CD62L-CD45RA-) CD4+T cells, which are associated with control TB. Furthermore, TB-IRIS patients had elevated CXCR3+CCR6+CD4+ T cells, which are thought to mediate a large portion of CD4+ anti-TB responses, and these CXCR3+CCR6+CD4+ T cells remained significantly elevated for at least 8 months after the initiation of ART. Based on our preliminary data, we hypothesize that the distinct cellular responses we observed in TB-IRIS may represent important protective responses to TB. We hypothesize that evaluating these responses in former CAMELIA patients cured of TB and on stable ART in a TB endemic environment will lead to identification of novel antigens important for protective responses and future vaccine development. Host biomarkers of TB infection, TB-IRIS and TB/HIV co-infection and linked clinical outcomes are lacking. Using RNA microarrays, we will determine signatures associated with TB co-infection, TB-IRIS, and antigen specific TB responsiveness. We hypothesize that this analysis in this extremely well-characterized patient cohort will provide robust and novel biomarkers of TB co- infection, containment of TB disease, and protective responses associated with in vitro assays. Finally, using archived PBMC, from TB+/ HIV+ patients from CAMELIA or TB-/HIV+ patients with similar baseline characteristics who began ART at the same time, we will test the hypothesis that TB co-infection and TB-IRIS modulate HIV reservoir tropism after ART initiation the months after ART initiation and years later and potentially also influence reservoir size. Findings from these experiments will be of great value for improving both treatment of TB/HIV co-infection and our general understanding of the host immune response to TB/HIV as well as providing the first evidence indicating that TB co-infection can affect the composition of the HIV reservoir.