Role of Zinc in HIV inflammation

 描述（由申请人提供）：有效的抗逆转录病毒治疗对HIV感染受试者的死亡率产生了令人印象深刻的影响，但这一成功是以牺牲显著的合并症为代价的，包括心血管疾病和糖尿病。这些合并症与炎症和单核细胞活化增强有关，但这种活化/炎症增强的病因尚未完全了解，但部分原因是肠道上皮屏障功能障碍和微生物易位。在HIV+治疗受试者中控制炎症、免疫激活或微生物易位的尝试在很大程度上是不成功的，即使是成功的治疗（如他汀类药物）也存在药物相互作用和安全性问题，可能会妨碍其在大部分HIV人群中的使用。现在非常需要能够更广泛地采用的更安全的战略。据世界卫生组织估计，在发展中国家有近20亿人可能缺锌。在发达国家，在有效的抗逆转录病毒疗法之前，锌缺乏在艾滋病毒感染者中普遍存在，并与疾病进展和较高的死亡率独立相关。与大多数营养素不同的是，锌缺乏的患病率仍然很高，即使在接受抗逆转录病毒治疗的受试者中也是如此。例如，健康生活营养研究发现，38%接受抗逆转录病毒治疗的受试者缺锌，锌水平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。到目前为止，缺乏与锌状态对HIV中炎症和单核细胞活化加剧的贡献相关的数据。此外，少数可用的HIV补锌研究大多数是在未经治疗或未经最佳治疗的受试者中进行的，并且没有研究评估了在ART病毒学抑制的HIV+受试者中补锌后炎症标志物的变化，这是当前HIV感染时代的相关人群，其中指南要求每个HIV+受试者进行积极治疗。在该提案的R21阶段，我们将评估接受ART的HIV感染受试者中锌缺乏的患病率，并将其与匹配的HIV阴性对照组进行比较。我们还将研究锌水平与全身炎症、先天免疫和肠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，在有记录的锌缺乏症的艾滋病毒感染者中测试两种不同剂量的锌补充剂。这项试点试验还将探索这种策略是否会影响选定的炎症标志物，并将有助于指导下一阶段的研究。在R33阶段，我们将在接受ART治疗的艾滋病毒感染受试者中进行一项锌补充剂的试点随机安慰剂对照研究，我们将评估锌补充剂是否安全有效地增加锌水平，以及它是否会影响与艾滋病毒合并症有关的不同途径，即先天免疫，全身炎症，氧化应激和肠道上皮屏障功能障碍。我们的建议应该提供重要的机制的见解，告知我们的作用机制，通过锌可能产生临床效益的艾滋病毒+人口，因此将提供必要的信息，以开发一个有竞争力的全面的临床试验。

 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.