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

胃肠道和相关组织 T 细胞的代谢编程对 HIV 储存库播种、维持和重新激活的影响

• 批准号: 10361609
• 负责人: CRISTIAN APETREI
• 金额: $ 79.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361609
• 关键词: Abbreviations; Adipose tissue; African Green Monkey; Anti-Retroviral Agents; Area; Automobile Driving; Berlin; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cancer Cell Growth; Cardiovascular system; Cell Survival; Cells; Cellular Metabolic Process; Chronic; Collaborations; Consensus; DNA; Data; Diet; Dietary Fats; Dietary Intervention; Dietary Sugars; Disease Progression; Elements; Environment; Epidemic; Fasting; Fatty acid glycerol esters; Fiber; Gastrointestinal tract structure; Goals; HIV; HIV Infections; HIV-1; Hematopoietic Stem Cell Transplantation; High Fat Diet; High-Throughput Nucleotide Sequencing; Human; Immune; Immune response; Immune system; Immunity; Industry; Infection; Inflammation; Inflammatory Bowel Diseases; Interruption; Intervention; Intravenous; Knowledge; Lead; Link; Lipids; London; Lymphoid Tissue; Macaca mulatta; Macaca nemestrina; Maintenance; Malignant Neoplasms; Metabolic; Metabolic Control; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mississippi; Nutritional; Pathogenesis; Pathologic; Pathway interactions; Patients; Persons; Plasma; Predisposition; Process; Production; Relapse; Reporting; Research; Residual state; Role; SIV; Scientific Advances and Accomplishments; Shapes; Site; T-Cell Depletion; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Tissues; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Work; antiretroviral therapy; base; dietary; exhaust; gastrointestinal; gut health; gut microbiome; host microbiome; immune activation; improved; inhibitor/antagonist; innovation; metabolic profile; microbial; microbiome; microbiome alteration; nonhuman primate; prognostic; programs; response; sugar; tool; western diet

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.

两个根除病毒的案例(“柏林病人”和“伦敦病人”)证明了治愈艾滋病毒的方法 感染是可行的。与此同时，艾滋病毒流行病的负担有增无减，因此 艾滋病病毒携带者(PLWH)开始抗逆转录病毒治疗(ART)，两人新感染，燃料 全球的共识是，需要治愈艾滋病毒来遏制疫情。根除的限制因素是：(1) HIV在免疫反应看不见的潜伏感染细胞中的持久性，(Ii)无法破坏/耗尽 免疫系统消除艾滋病毒感染细胞，以及(3)持续存在的慢性炎症状态 抛开艺术不谈。更好地了解艾滋病毒储存库的播种、维护和重新激活将发现新的 有效根除病毒的战略。我们报道，饮食可能会干扰SIV的复制、免疫 激活(IA)/INFL、微生物组、基本代谢特征和疾病进展。饮食直接影响和 间接影响宿主代谢、调节免疫反应和预测HIV感染的预后。我们也 报告了细胞代谢编程对推动艾滋病毒持续存在的所有关键方面的重大影响：(I) 艾滋病毒感染的易感性、感染细胞的持久性和潜伏期的建立。(二)质量 以及对艾滋病毒的免疫反应的大小。(Iii)与艾滋病毒感染有关的非传染性疾病，导致宿主 维持(通过潜伏感染细胞的持续增殖)及其在组织中的补充。最后， 我们报告说，免疫细胞编程的代谢变化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) 这可能会极大地影响艾滋病毒的发病机制，并影响艾滋病毒蓄水池的播种、维护和重新激活， 它可以通过饮食来补充能量。目前正在探索禁食和饮食干预措施，单独或在 在多种其他病理情况下与代谢抑制剂联合使用。我们将探讨这一假说 给猕猴喂西式饮食(WD，即富含脂肪和糖)将为SIV提供燃料 通过肠道和相关T细胞的变化，储藏的形成、维持和再激活 淋巴组织和肾上腺皮质激素。我们将评估WD对宿主微生物群、新陈代谢、免疫的整体影响 细胞代谢编程、免疫反应、IA/INFL，我们将这些参数与储存库相关联 播种、维护和重新激活。我们将进一步确定肠道T细胞是否对 由WD或已知变化引发的饮食糖脂变化、血糖和血脂增加 在由WD驱动的肠道微生物群中。我们还将使用他汀类药物在治疗上逆转WD相关的过程。自.以来 在我们的初步研究中报告的关键变化似乎集中在胃肠道(GI)， HIV复制和CD4+T细胞耗尽的主要部位，我们将重点放在肠道和邻近的淋巴组织 和ADTS。血液将被用作胃肠道区域变化的系统比较器。这些研究可能会确定 遏制艾滋病毒宿主、逆转代谢功能障碍和控制残留感染的新战略。