Determining the interplay of MAIT cells and the translocated microbiome in HIV-induced neuroinflammation

总结/摘要 用抑制性ART治疗HIV的重大进展导致了长期的病毒抑制; 然而，HIV感染者（PLWH）继续经历CNS紊乱，包括HIV相关的 神经认知障碍（HAND）。持续的CNS免疫激活是HIV神经发病机制的标志， 即使在接受抑制性ART的PLWH中也持续存在。 艾滋病毒感染者（PLWH）和持续的神经系统疾病，尽管ART强调了重要性， 肠-脑通讯在PLWH中枢神经系统（CNS）共病发病机制中的作用。 然而，关于免疫学、微生物和中枢神经系统的同一性的问题 造成这种串扰的元件仍然不清楚。我们对粘膜相关不变T细胞的研究 (MAIT细胞），其是能够识别由MHC-1呈递的保守细菌配体的先天样T细胞。 在HIV-1感染期间，MAIT相关1（MR 1）分子的表达已经表明MAIT细胞在感染期间早期被激活 并在血液和结肠粘膜中扩张，与病毒血症高峰同时发生， 微生物易位此外，我们的初步单细胞转录组和TCR测序数据， 一组在PLWH的脑脊液（CSF）中检测到大比例的MAIT细胞，提示MAIT细胞 可能作为肠-脑轴的免疫介质。然而，MAIT细胞免疫介导的肠-脑轴 HIV感染的机制尚未研究。我们假设MAIT细胞是一种主要的免疫细胞类型 介导肠道生态失调、微生物易位、免疫细胞功能障碍和CNS共- PLWH的发病率。为了全面研究包括CNS在内的跨隔室的MAIT细胞，我们将 利用已采集的肠道生物标本、冻存外周血单核细胞、血浆、CSF 来自先前非人灵长类动物的液体、冷冻保存的CSF细胞团和死后脑组织样本 由MHRP使用SHIV-1157 ipd 3 N4进行的研究。在目标1中，我们将纵向比较和对比 SHIV期间肠道微生物组与驻留在CSF、血液、肠道和脑中的MAIT细胞之间的关系 感染、ART后和分析治疗中断后。在目标2中，我们将确定 在MAIT-神经细胞相互作用后易位的微生物组。总的来说，这项R21提案的结果可以 尽管ART抑制了病毒，但为PLWH伴神经系统疾病开辟了新的免疫治疗途径 通过靶向MAIT细胞作为肠-脑轴的关键免疫介质之一。

Summary/Abstract Significant progress in the treatment of HIV with suppressive ART has led to long term viral suppression; however, people living with HIV (PLWH) continue to experience CNS perturbations including HIV-associated neurocognitive disorders (HAND). Persistent CNS immune activation is a hallmark of HIV neuropathogenesis, and persists even in PLWH who are on suppressive ART. The identification of persistent intestinal dysbiosis in people living with HIV (PLWH) and ongoing neurological disorders despite ART has highlighted the importance of gut–brain communication in the pathogenesis of central nervous system (CNS) co-morbidities in PLWH. However, the question regarding the identity of immunological, microbial, and central nervous system components responsible for this crosstalk remains unclear. Our studies of mucosal-associated invariant T cells (MAIT cells), which are innate-like T cells able to recognize conserved bacterial ligands presented by MHC- related 1 (MR1) molecule, during HIV-1 infection have shown that MAIT cells are activated early during infection and expand in blood and colonic mucosa coincident with peak viremia, in a manner associated with emerging microbial translocation. Moreover, preliminary single cell transcriptomic and TCR sequencing data from our group has detected a large proportion of MAIT cells in cerebrospinal fluid (CSF) of PLWH, suggesting MAIT cells may serve as immune mediator of the gut-brain axis. Yet, a MAIT cell immune mediated gut-brain axis mechanism has not been studied in HIV infection. We hypothesize that MAIT cells are a major immune cell type that mediate the crosstalk between gut dysbiosis, microbial translocation, immune cell dysfunction, and CNS co- morbidities in PLWH. To comprehensively study MAIT cells across compartments including the CNS, we will leverage already collected biospecimens of gut, cryopreserved peripheral blood mononuclear cells, plasma, CSF fluid, cryopreserved CSF cell pellets, and postmortem brain tissues samples from a previous non-human primate study conducted by MHRP using SHIV-1157ipd3N4. In Aim 1, we will longitudinally compare and contrast the relationship between the gut microbiome to the MAIT cells residing in CSF, blood, gut, and brain during SHIV infection, post ART, and following analytical treatment interruption. In aim 2, we will determine the effects of translocated microbiome upon MAIT-neural cell interactions. Overall, the findings from this R21 proposal could open new immunotherapy avenues for PLWH with neurological disorders despite virological suppression by ART by targeting MAIT cells as one of the key immune mediators of the gut-brain axis.