Chronic Widespread Pain in HIV: Novel Mechanisms and Therapeutics

项目摘要/摘要 新疗法的出现和使用使感染人类免疫缺陷病毒(HIV)成为一种 慢性疾病，使患者拥有接近正常的预期寿命。然而，慢性病的患病率 尽管病毒载量很低，但艾滋病毒感染者的广泛性疼痛(CWP)很高，从25%到85%不等 和足够的CD4细胞计数。煤工尘肺是HIV感染最常见的相关并发症之一， 与高伤残率和生活质量下降有关。然而，具体的机制是 在艾滋病毒中对煤工尘肺有贡献的人还不清楚。因此，药理学和非药理学的方法 减轻CWP的益处微乎其微，导致对阿片类药物的过度依赖和成瘾的惊人上升 还有服药过量。这项建议的总体目标是解决对发病机制认识上的差距。 并确定潜在的生物标志物和治疗靶点，以减轻HIV中的CWP。具体来说，我们将 探讨游离亚铁血红素在内源性阿片合成/释放障碍中的作用 煤工尘肺患者外周血白细胞的检测我们新的初步发现表明，自我保护的HIV患者 有报道称，患有煤工尘肺的患者血浆中游离血红素水平升高，同时白细胞β-1降低。 相对于没有煤工尘肺的HIV患者，内啡肽水平。血红素是一种促炎分子，可以诱导 内质网应激，以及对白细胞功能的抑制。血红素也促进了M0的转变 巨噬细胞倾向于M1样的促炎表型，而不是M2样的前分解表型。与M2相比 细胞，M1巨噬细胞含有和释放较少的阿片肽。因此，我们假设 无细胞血红素减少内源性阿片肽依赖的镇痛作用，并增强PWH的疼痛敏感性。 我们将通过以下具体目标实现总体目标：1)建立直接联系 血浆中游离血红素浓度与外周血内阿片肽的定量关系 对患有煤工尘肺的HIV患者的感觉测量，2)通过翻译的方式确定其机制 哪种血红素有助于减少外周阿片类药物的释放和疼痛，以及3)测试是否清除血红素 是一种增加白细胞内源性阿片类药物和减轻疼痛过敏的治疗选择。这部作品 是新的，因为白细胞内源性阿片肽的合成和释放对HIV中CWP的影响 以前从未被直接检查过。此外，拟议的工作具有创新性，因为它结合了临床 以及临床前实验，包括使用HIV-1转基因大鼠模型来识别潜在的生物标记物 以及CWP在HIV中的作用机制。这项拟议的研究意义重大，因为如果我们的假设得到证实， 我们将确定：1)血红素是艾滋病毒疼痛的主要驱动因素，2)血红素清除血红素是一种新的方法， 艾滋病毒相关疼痛的非阿片类药物治疗。

PROJECT SUMMARY/ABSTRACT The advent and access to new treatments have made infection with human immunodeficiency virus (HIV) a chronic disease, allowing patients to have a nearly normal life expectancy. However, the prevalence of chronic widespread pain (CWP) in individuals infected with HIV is high, ranging from 25% to 85%, despite low viral load and adequate CD4 count. CWP is one of the most common associated comorbidities of HIV infection and is associated with high rate of disability and decreased quality of life. However, the specific mechanisms that contribute to CWP in HIV are not understood. Thus, pharmacological and non-pharmacological approaches to mitigate CWP have had minimal benefits, contributing to an overreliance on opioids and alarming rise in addiction and overdose. The overall objective of this proposal is to address the gap in the knowledge of the pathogenesis of CWP and identify potential biomarkers and therapeutic targets to mitigate CWP in HIV. Specifically, we will explore the role of cell-free heme in impairment of endogenous opioid synthesis/release from peripheral leukocytes in HIV patients with CWP. Our novel preliminary findings demonstrate that HIV patients who self- report having CWP have elevated plasma levels of cell-free heme, coupled with decreased leukocyte β- endorphin levels, relative to HIV patients without CWP. Heme is a pro-inflammatory molecule that can induce endoplasmic reticulum stress, as well as inhibit function of leukocytes. Heme also promotes the transition of M0 macrophages toward an M1-like pro-inflammatory rather than M2-like proresolution phenotype. Compared to M2 cells, M1 macrophages contain and release lower amounts of opioid peptides. Therefore, we hypothesize that cell-free heme reduces endogenous opioid peptide-dependent analgesia and enhances pain sensitivity in PWH. We will accomplish our overall objective by addressing the following specific aims: 1) establish a direct link between plasma concentration of cell-free heme and peripheral endogenous opioid peptides with quantitative sensory measures in HIV patients with CWP, 2) to determine in a translational manner the mechanisms through which heme contributes to diminished peripheral opioid release and pain, and 3) test whether heme scavenging is a therapeutic option to increase leukocyte endogenous opioids and attenuate pain hypersensitivity. This work is novel as the impact of endogenous opioid peptide synthesis and release by leukocytes on CWP in HIV has never before been directly examined. Furthermore, the proposed work is innovative in that it combines clinical and preclinical experiments, including the use of the HIV-1 transgenic rat model, to identify potential biomarkers and mechanisms of CWP in HIV. The proposed research is significant because, if our hypotheses are confirmed, we will identify: 1) heme as a major driver of pain in HIV, and 2) heme scavenging by hemopexin as a novel, non-opioid therapeutic for HIV-associated pain.