Role of Zinc in HIV inflammation

 描述(申请人提供)：有效的抗逆转录病毒疗法对艾滋病毒感染者的死亡率产生了令人印象深刻的影响，但这一成功是以严重的共病为代价的，包括心血管疾病和糖尿病。这些共病与炎症和单核细胞激活增加有关，但这种激活/炎症增加的原因尚不完全清楚，但部分原因是肠道上皮屏障功能障碍和微生物易位。在HIV+治疗的受试者中，控制炎症、免疫激活或微生物易位的尝试大多不成功，即使是已经成功的治疗(如他汀类药物)也存在药物相互作用和安全问题，可能会阻止它们在很大一部分艾滋病毒人群中使用。我们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，发展中国家可能有近20亿人患有锌缺乏。在发达国家，在有效的抗逆转录病毒疗法之前，缺锌在艾滋病毒感染者中普遍存在，并与疾病进展和更高的死亡率独立相关。与大多数营养素观察到的情况不同，缺锌的患病率仍然很高，即使是在ART的受试者中也是如此。例如，营养促进健康生活研究发现，接受抗逆转录病毒治疗的受试者中有38%缺锌，而锌水平高四分之一的受试者HIV-1RNA水平低于锌水平最低四分位数的受试者。到目前为止，缺乏与锌状态对艾滋病毒炎症和单核细胞激活加剧的贡献有关的数据。此外，为数不多的针对HIV的锌补充研究大多是在未经治疗或未进行最佳治疗的受试者中进行的，还没有研究评估在对ART进行病毒学抑制的HIV+受试者补锌后炎症标志物的变化，ART是与当前HIV感染时代相关的人群，指南呼吁对每一名HIV+受试者进行积极治疗。在建议的R21阶段，我们将评估接受抗逆转录病毒治疗的艾滋病毒感染者中锌缺乏的患病率，并将其与艾滋病毒阴性对照的匹配组进行比较。我们还将研究锌水平与全身炎症、先天免疫和肠道上皮屏障功能障碍的关系。最后，我们将进行一项先导性研究，测试两种不同剂量的锌补充剂对患有有据可查的锌缺乏症的艾滋病毒感染者的作用。这项试点试验还将探索这一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，我们将在患有缺锌的HIV感染者中进行一项试验性的安慰剂对照研究，评估补锌是否安全有效，提高锌水平，以及是否会影响与HIV共生相关的不同途径，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械性见解，让我们了解锌可能在HIV+人群中产生临床益处的作用机制，并因此提供必要的信息，以开发具有竞争力的全面临床试验。

 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.