Role of Zinc in HIV inflammation

锌在 HIV 炎症中的作用

• 批准号: 9902711
• 负责人: GRACE A MCCOMSEY
• 金额: $ 24.14万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902711
• 关键词: Adopted; Adult; Affect; Age; Alcohol consumption; Biological; CD4 Lymphocyte Count; Calories; Cardiovascular Diseases; Clinical; Clinical Trials; Comorbidity; Cross-Sectional Studies; Data; Developed Countries; Developing Countries; Diabetes Mellitus; Diet; Disease; Disease Progression; Dose; Drug Interactions; Epithelial; Etiology; Frequencies; Functional disorder; General Population; Guidelines; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV therapy; HIV-1; Health Benefit; High Prevalence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin Resistance; Investigation; Link; Malignant Neoplasms; Matched Group; Measures; Natural Immunity; Nutrient; Obesity; Oxidative Stress; Pathway interactions; Phase; Pilot Projects; Population; Prevalence; Public Health; RNA; Research Personnel; Rheumatoid Arthritis; Risk; Role; Safety; Testing; Zinc; Zinc deficiency; Zinc supplementation; antiretroviral therapy; dietary supplements; immune activation; improved; inflammatory marker; insight; medication safety; microbial; monocyte; mortality; novel; nutrition; pilot trial; pre-clinical; public health relevance; randomized placebo controlled trial; repaired; success; virology

 DESCRIPTION (provided by applicant): Potent antiretroviral therapy has had an impressive impact on mortality in HIV-infected subjects, but this success came at the expense of significant co-morbidities, including cardiovascular disease and diabetes. These co-morbidities have been linked to heightened inflammation and monocyte activation, but the etiology of this heightened activation/inflammation is not fully understood, but is partly due to gut epithelial barrier dysfunction and microbial translocation. Attempts at controlling inflammation, immune activation or microbial translocation in HIV+ treated subjects have been for the most part unsuccessful, and even treatment that have been successful (such as statins) have drug interactions and safety concerns, likely precluding their use in a large proportion of the HIV population. Safer strategies that could be more widely adopted are well needed. It has been estimated by the WHO that nearly two billion subjects may be zinc deficient in the developing countries. In the developed countries, prior to effective ART, zinc deficiency was prevalent in HIV-infected subjects, and had been independently linked to disease progression and to higher mortality. Unlike what is observed with most nutrients, the prevalence of zinc deficiency continues to be high, even in subjects on ART. For example, the Nutrition for Healthy Living study found that 38% of subjects on ART had zinc deficiency, and subjects in the upper quartiles of zinc levels had lower HIV-1 RNA levels than those in the lowest quartile. Thus far, there is a lack of data related to the contribution of zinc status to the heightened inflammation and monocyte activation in HIV. Also, the few available zinc-supplementation studies in HIV have been mostly in untreated or not optimally treated subjects, and no studies have assessed changes in inflammation markers after zinc supplementation in HIV+ subjects with virologic suppression on ART, a pertinent population to the current era of HIV infection where guidelines are calling for every HIV+ subject to be aggressively treated. In the R21 phase of the proposal, we will assess the prevalence of zinc deficiency in HIV-infected subjects on ART and compare it to that of a matched group of HIV negative controls. We will also study the relationships between zinc levels and systemic inflammation, innate immunity and gut epithelial barrier dysfunction. Lastly, we will conduct a pilot study testing two different doses of zinc supplementation in HIV-infected subjects on ART with documented zinc deficiency. This pilot trial will also explore whether this strategy may affect selected inflammation markers and will help guide the next phase of investigations. In the R33 phase, we will conduct a pilot randomized placebo-controlled study of zinc supplementation in HIV-infected subjects on ART with zinc deficiency, and we will assess whether zinc supplementation is safe and effective at increasing zinc levels, and whether it will affect different pathways involved in HIV-comorbidities, namely innate immunity, systemic inflammation, oxidative stress, and gut epithelial barrier dysfunction. Our proposal should provide important mechanistic insights to inform us on the mechanism of action through which zinc may produce clinical benefit in the HIV+ population, and as such will provide the information necessary to develop a competitive full-scale clinical trial.

 描述（由适用提供）：有效的抗逆转录病毒疗法对感染HIV感染的受试者的死亡率产生了令人印象深刻的影响，但是这一成功是以重要的合并症为代价的，包括心血管疾病和糖尿病。这些合并症与感染和单核细胞激活的增强有关，但是这种增强激活/炎症的病因尚未完全了解，但部分是由于肠道上皮屏障功能障碍和微生物翻译。在HIV+治疗受试者中控制炎症，免疫激活或微生物翻译的尝试在很大程度上是不成功的，甚至成功的治疗（例如他汀类药物）具有药物相互作用和安全性问题，可能无法在很大一部分HIV人群中使用。需要更广泛地采用的更安全的策略。据估计，谁在发展中国家可能会占锌的锌不足。在发达国家，在有效的ART之前，锌缺乏症在受HIV感染的受试者中普遍存在，并且与疾病的进展和更高的死亡率有关。与大多数营养物质所观察到的不同，即使在ART受试者中，锌缺乏症的流行率也仍然很高。例如，《健康生活研究​​的营养》发现，38％的ART受试者缺乏锌缺乏，而锌水平的上四分位数的受试者的HIV-1 RNA水平低于最低四分位数的受试者。这远，缺乏与锌状态对艾滋病毒感染增强和单核细胞激活的贡献有关的数据。另外，HIV中少数可用的锌支持研究主要是未经治疗或未经最佳治疗的受试者，并且在补充HIV+受试者对ART病毒抑制的锌+受试者中锌的炎症标志物的变化尚未评估，这是对ART的抑制，这是对HIV感染的当前人群的指导时代，该指南对每个指导率进行了hiv+ a受试者+ hiv+ a hiv+ a hiv+均具有优化的治疗。在该提案的R21阶段，我们将评估ART中HIV感染受试者中锌缺乏症的流行率，并将其与匹配的HIV阴性对照组的患病率进行比较。我们还将研究锌水平与全身感染，先天免疫和肠道上皮屏障功能障碍之间的关系。最后，我们将进行一项试点研究，测试具有锌缺乏症的ART中的两种不同剂量的HIV感染受试者中补充锌。该试验试验还将探讨该策略是否可能影响选定的感染标志物，并将有助于指导下一阶段的调查。在R33阶段，我们将进行一项试验性安慰剂对照研究，对艾滋病毒感染受试者的锌补充受试者的锌不足受试者的补充研究，我们将评估补充锌的补充是安全有效的锌水平上的安全有效，以及它是否会影响艾滋病毒的不同途径，是否会影响艾滋病毒的不同途径功能障碍。我们的建议应提供重要的机械见解，以告知我们有关锌可以在HIV+人群中产生临床益处的作用机理，因此，将提供开发有竞争力的全尺度临床试验所需的信息。