Chronic Widespread Pain in HIV: Novel Mechanisms and Therapeutics

项目总结/摘要 新疗法的出现和获得使人类免疫缺陷病毒（艾滋病毒）感染成为一种流行病。 慢性病，使患者有一个接近正常的预期寿命。然而，慢性 尽管病毒载量较低，但感染HIV的个体的广泛性疼痛（CWP）较高，范围为25%至85% 以及足够的CD 4计数。CWP是HIV感染最常见的合并症之一， 与高残疾率和生活质量下降有关。然而，具体的机制， 对CWP在HIV中的作用尚不清楚。因此，药理学和非药理学方法， 缓解CWP的好处微乎其微，导致对阿片类药物的过度依赖和成瘾率的惊人上升 还有吸毒过量该提案的总体目标是解决发病机制知识方面的差距 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 探讨游离血红素在外周血内源性阿片合成/释放障碍中的作用 白细胞在HIV患者CWP。我们的新的初步研究结果表明，艾滋病患者谁自我- 有报道称，CWP患者血浆中游离血红素水平升高，同时白细胞β- 内啡肽水平，相对于没有CWP的HIV患者。血红素是一种促炎分子， 内质网应激以及抑制白细胞功能。血红素还促进了M0的转变 巨噬细胞向M1样促炎表型而不是M2样促消退表型转化。与M2相比 细胞，M1巨噬细胞含有并释放较少量的阿片肽。因此，我们假设， 无细胞血红素减少内源性阿片肽依赖性镇痛并增强PWH的疼痛敏感性。 我们将通过以下具体目标实现我们的总体目标：1）建立直接联系 血浆游离血红素浓度与外周内源性阿片肽之间的定量关系 感觉措施在艾滋病毒患者与CWP，2）以确定在翻译的方式机制，通过 其中血红素有助于减少外周阿片样物质释放和疼痛，以及3）测试血红素清除是否 是增加白细胞内源性阿片样物质和减弱疼痛超敏性治疗选择。这项工作 是新的，因为内源性阿片肽的合成和释放的影响，白细胞对CWP的艾滋病毒， 从未被直接检查过。此外，所提出的工作是创新的，因为它结合了临床 和临床前实验，包括使用HIV-1转基因大鼠模型，以确定潜在的生物标志物 和HIV中CWP的机制。这项研究是重要的，因为如果我们的假设得到证实， 我们将确定：1）血红素是HIV疼痛的主要驱动因素，和2）血红素结合蛋白清除血红素是一种新的， 非阿片类药物治疗HIV相关疼痛。

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.