Impact of metabolic programing of T cells from the GI tract and related tissues on HIV reservoir seeding, maintenance and reactivation

两例病毒根除病例（"柏林患者"和"伦敦患者"）表明， 感染是可行的。与此同时，艾滋病毒流行病的负担有增无减， 艾滋病毒感染者（PLWH）开始抗逆转录病毒治疗（ART），两个新的人成为感染者，燃料 全球一致认为，需要治愈艾滋病毒，以遏制这一流行病。根除的限制因素有： HIV在潜伏感染细胞中的持续存在对免疫应答是不可见的，（ii）受损/耗尽的免疫应答细胞不能产生免疫应答。 免疫系统以消除HIV感染的细胞，以及（iii）持续存在的慢性炎症（INFL）状态 更好地了解艾滋病毒库的播种，维持和重新激活将确定新的 有效根除病毒的战略。我们报道了饮食可能会干扰SIV的复制，免疫 在一些实施方案中，所述方法包括使用免疫调节因子（IA）/INFL、微生物组、基本代谢特征和疾病进展来评估免疫调节因子。饮食直接影响， 间接调节宿主代谢，调节免疫应答和HIV感染的预后。我们也 报告了细胞代谢程序对驱动艾滋病毒持久性的所有关键方面的重大影响：（i） HIV靶点对感染的易感性、感染细胞的持续性和潜伏期的建立。(ii)质量 以及对艾滋病病毒免疫反应的强度。(iii)与HIV感染相关的INFL，有助于储存 维持（通过潜伏感染细胞的持续增殖）和在组织中的补充。最后， 我们报道了免疫细胞编程的代谢改变可以优先发生在肠道中。 总之，我们的研究结果定义了一个轴（饮食→微生物组→营养代谢→免疫代谢） 可以显著影响HIV发病机制并形成HIV储存库播种、维持和再激活， 并且可以通过饮食来补充。禁食和饮食干预目前正在探索，单独或联合 在多种其他病理状况下与代谢抑制剂组合。我们将探讨这个假设 西方饮食（WD，即，富含脂肪和糖）， 通过肠道和相关组织中T细胞的变化， 淋巴和AdTs。我们将评估WD对宿主微生物组、代谢、免疫和免疫系统的总体影响。 细胞代谢程序，免疫反应，IA/INFL，我们将这些参数与水库 播种、维护和恢复。我们将进一步确定肠道T细胞是否对A 饮食中糖和脂质的变化，由WD触发的血糖和脂质增加，或已知的变化 由WD驱动的肠道微生物组。我们还将用他汀类药物治疗性逆转WD相关过程。以来 在我们的初步研究中报道的关键改变似乎以胃肠道（GI）为中心， HIV复制和CD4 + T细胞耗竭的主要部位，我们将重点放在肠道和邻近的淋巴 AdTs。血液将用作GI区域变化的全身比较物。这些研究可以识别 新的策略，以遏制艾滋病毒水库，扭转代谢功能障碍和控制残留的INFL。

Two cases of virus eradication (the “Berlin patient” and the “London patient”) demonstrated that a cure for HIV infection is feasible. Meanwhile, the burden of the HIV epidemic, which spreads unabated, as such that for every person living with HIV (PLWH) that starts antiretroviral therapy (ART), two new people become infected, fuels the global consensus that a cure for HIV is needed to curb the epidemic. Limitations towards eradication are: (i) HIV persistence in latently infected cells invisible to immune responses, (ii) inability of a damaged/exhausted immune system to eliminate HIV-infected cells, and (iii) a state of chronic inflammation (INFL) that persists despite ART. A better understanding of HIV reservoir seeding, maintenance and reactivation will identify new strategies for effective virus eradication. We reported that diet may interfere with SIV replication, immune activation (IA)/INFL, microbiome, basic metabolic features, and disease progression. Diet impacts directly and indirectly the host metabolism, modulating immune responses and the prognostic of HIV infection. We also reported a major impact of cell metabolic programing on all the key aspects that drive HIV persistence: (i) susceptibility to infection of HIV targets, persistence of infected cells, and the establishment of latency. (ii) Quality and magnitude of the immune responses to HIV. (iii) INFL associated to HIV infection, that contribute to reservoir maintenance (through continuous proliferation of latently infected cells) and its replenishment in tissues. Finally, we reported that metabolic alterations of the immune cell programing can preferentially occur in the gut. Altogether our results studies define an axis (diet→microbiome→nutritional metabolism→immunometabolism) that can dramatically impact HIV pathogenesis and shape HIV reservoir seeding, maintenance and reactivation, and which can be fueled by diet. Fasting and dietary interventions are being currently explored, alone or in combination with metabolic inhibitors in multiple other pathological conditions. We will probe the hypothesis that administration of a Western diet (WD, i.e., rich in fat and sugars) to rhesus macaques will fuel SIV reservoir formation, maintenance, and reactivation, through changes in T cells from the gut and related lymphoid and AdTs. We will assess the overall impact of the WD on host microbiome, metabolism, immune cell metabolic programing, immune responses, IA/INFL, and we will correlate these parameters with reservoir seeding, maintenance and reactivation. We will further determine whether gut T cells are responding to either a change in dietary sugars and lipids, plasma sugar and lipid increases trigerred by the WD, or to known changes in gut microbiome driven by WD. We will also therapeutically revert the WD-related processes with statins. Since the key alterations reported in our preliminary studies appeared to be centered by the gastrointestinal (GI) tract, the main site of HIV replication and CD4+ T cell depletion, we will focus on the gut and the adjacent lymphoid and AdTs. Blood will be used as a systemic comparator to alterations in the GI area. These studies may identify new strategies to curb the HIV reservoir, reverse the metabolic dysfunctions and control residual INFL.