HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System.
HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System.
复制标题
DOI：
10.1007/s11481-020-09927-6
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Berman JW
中科院分区：
文献类型：
--
作者：
Nickoloff-Bybel EA;Calderon TM;Gaskill PJ;Berman JW
抗逆转录病毒疗法（ART）已将艾滋病毒转化为慢性疾病，延长和改善了这种病毒感染者的生命。尽管成功地抑制了HIV复制，但HIV感染者（PLWH）易患越来越多的合并症，包括由中枢神经系统（CNS）感染引起的神经HIV。多巴胺能系统的改变长期以来与CNS的HIV感染有关。研究表明，多巴胺浓度的变化不仅改变神经传递，而且还显著影响免疫细胞的功能，导致神经炎症和神经元功能障碍。单核细胞/巨噬细胞是CNS中HIV的主要靶标，对多巴胺有反应。因此，更精确地定义多巴胺作用于这些细胞的机制，以及这种神经递质引起的细胞功能的变化，对于开发治疗神经HIV的治疗策略是必要的。这对于具有化学改变的多巴胺浓度的PLWH弱势群体尤其重要，例如患有物质使用障碍（SUD）的个体或使用多巴胺改变药物的老年人。CNS多巴胺增加的具体神经病理学和神经认知后果尚不清楚。这是由于HIV神经发病机制的复杂性，以及导致队列研究、动物模型和体外研究之间不一致的后勤和技术挑战，以及缺乏人口统计学数据和获得人类CNS样本和细胞的机会。本文综述了目前的认识多巴胺对HIV neuropathogenesis的影响，并提出了新的实验方法来研究多巴胺在中枢神经系统HIV infection.Graphical abstractHIV Neuropathogenesis的作用在多巴胺系统中断的存在。物质滥用障碍和使用多巴胺能药物治疗年龄相关疾病均与CNS多巴胺浓度和多巴胺能神经传递的变化相关。这些变化可能导致异常的免疫功能，特别是在骨髓细胞中，这有助于在HIV+个体中富含多巴胺的区域中观察到的神经炎症，神经病理学和神经传递功能障碍。尽管使用抗逆转录病毒疗法（ART），这些变化仍然可见，反过来又导致多巴胺系统的进一步失调。因此，在多巴胺升高的个体中，异常多巴胺能神经传递和HIV感染之间的双向相互作用产生了一个反馈回路，导致HIV相关的神经认知功能障碍和neuroHIV。然而，HIV感染、炎症介质、ART、药物滥用和年龄相关治疗的独特贡献和相互作用却知之甚少。更精确地定义这些因素影响神经系统疾病发展的机制对于解决neuroHIV在脆弱人群（如艾滋病毒感染的老年人或吸毒者）中的持续存在至关重要。由于这一系统的复杂性，了解这些影响将需要结合新的实验模式，在艺术的背景下，这些将包括更严格的流行病学研究，相关的动物模型，和体外细胞和分子机制分析。
Antiretroviral therapy (ART) has transformed HIV into a chronic condition, lengthening and improving the lives of individuals living with this virus. Despite successful suppression of HIV replication, people living with HIV (PLWH) are susceptible to a growing number of comorbidities, including neuroHIV that results from infection of the central nervous system (CNS). Alterations in the dopaminergic system have long been associated with HIV infection of the CNS. Studies indicate that changes in dopamine concentrations not only alter neurotransmission, but also significantly impact the function of immune cells, contributing to neuroinflammation and neuronal dysfunction. Monocytes/macrophages, which are a major target for HIV in the CNS, are responsive to dopamine. Therefore, defining more precisely the mechanisms by which dopamine acts on these cells, and the changes in cellular function elicited by this neurotransmitter are necessary to develop therapeutic strategies to treat neuroHIV. This is especially important for vulnerable populations of PLWH with chemically altered dopamine concentrations, such as individuals with substance use disorder (SUD), or aging individuals using dopamine-altering medications. The specific neuropathologic and neurocognitive consequences of increased CNS dopamine remain unclear. This is due to the complex nature of HIV neuropathogenesis, and logistical and technical challenges that contribute to inconsistencies among cohort studies, animal models andin vitrostudies, as well as lack of demographic data and access to human CNS samples and cells. This review summarizes current understanding of the impact of dopamine on HIV neuropathogenesis, and proposes new experimental approaches to examine the role of dopamine in CNS HIV infection.Graphical abstractHIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. Both substance abuse disorders and the use of dopaminergic medications for age-related diseases are associated with changes in CNS dopamine concentrations and dopaminergic neurotransmission. These changes can lead to aberrant immune function, particularly in myeloid cells, which contributes to the neuroinflammation, neuropathology and dysfunctional neurotransmission observed in dopamine-rich regions in HIV+ individuals. These changes, which are seen despite the use antiretroviral therapy (ART), in turn lead to further dysregulation of the dopamine system. Thus, in individuals with elevated dopamine, the bi-directional interaction between aberrant dopaminergic neurotransmission and HIV infection creates a feedback loop contributing to HIV associated neurocognitive dysfunction and neuroHIV. However, the distinct contributions and interactions made by HIV infection, inflammatory mediators, ART, drugs of abuse, and age-related therapeutics are poorly understood. Defining more precisely the mechanisms by which these factors influence the development of neurological disease is critical to addressing the continued presence of neuroHIV in vulnerable populations, such as HIV-infected older adults or drug abusers. Due to the complexity of this system, understanding these effects will require a combination of novel experimental modalities in the context of ART. These will include more rigorous epidemiological studies, relevant animal models, andin vitrocellular and molecular mechanistic analysis.
登录
查看更多内容
影响因子：
2.9
作者：
Boender TS;Smit C;Sighem AV;Bezemer D;Ester CJ;Zaheri S;Wit FWNM;Reiss P;ATHENA national observational HIV cohort
通讯作者：
ATHENA national observational HIV cohort
影响因子：
3.2
作者：
Becker, James T.;Sanders, Joanne;Madsen, Sarah K.;Ragin, Ann;Kingsley, Lawrence;Maruca, Victoria;Cohen, Bruce;Goodkin, Karl;Martin, Eileen;Miller, Eric N.;Sacktor, Ned;Alger, Jeffery R.;Barker, Peter B.;Saharan, Priyanka;Carmichael, Owen T.;Thompson, Paul M.
通讯作者：
Thompson, Paul M.
影响因子：
3.7
作者：
Ann HW;Jun S;Shin NY;Han S;Ahn JY;Ahn MY;Jeon YD;Jung IY;Kim MH;Jeong WY;Ku NS;Kim JM;Smith DM;Choi JY
通讯作者：
Choi JY
影响因子：
3.7
作者：
Bak Y;Jun S;Choi JY;Lee Y;Lee SK;Han S;Shin NY
通讯作者：
Shin NY
影响因子：
2.6
作者：
Akang, Edidiong N.;Dosumu, Olufunke O.;Akanmu, Alani S.
通讯作者：
Akanmu, Alani S.