研究 HIV-1 蛋白 Tat 和吗啡对脑内抗逆转录病毒药物的积累和分布的影响。

IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Austin M. Jones, Kara M. Rademeyer, Elias P. Rosen, Silas Contaifer, Dayanjan Wijesinghe, Kurt F. Hauser, MaryPeace McRae
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引用次数: 0

摘要

尽管抗逆转录病毒联合疗法能有效抑制外周的艾滋病病毒,但神经获得性艾滋病病毒(neuroHIV)仍然是一个严重的问题,大约一半的艾滋病病毒感染者会出现艾滋病相关神经认知障碍(HAND)。同时使用阿片类药物会促进神经炎症、神经元损伤和突触树突状细胞凋亡、病毒复制,并可能改变脑内抗逆转录病毒药物的浓度,从而加剧神经获得性艾滋病病毒(neuroHIV)的病情。本研究利用红外-基质辅助激光解吸电喷雾离子化质谱成像(IR-MALDESI MSI)技术,研究了在 HIV-1 Tat 转基因小鼠模型中,HIV 和吗啡共同暴露对脑内多个区域抗逆转录病毒药物的积累和空间分布的影响。暴露于吗啡会独特地降低大脑前部(初级运动和躯体感觉)皮层、胼胝体(前镊子)、尾突、伏隔核以及包括海马、胼胝体(主体)、大脑皮层(躯体感觉和听觉皮层)、丘脑和下丘脑在内的后部区域的抗逆转录病毒浓度。有趣的是,与雌性小鼠相比,雄性小鼠的抗逆转录病毒浓度因吗啡而下降的幅度更大。研究还评估了抗逆转录病毒浓度的变化是否与星形胶质细胞的炎症有关,评估的方法是使用胶质纤维酸性蛋白(GFAP)作为标记物测量星形胶质细胞的活化。抗逆转录病毒药物浓度的变化与星形胶质细胞活化区域的变化呈现出性别特异性治疗差异。这项研究强调了中枢神经系统内艾滋病病毒、阿片类药物和抗逆转录病毒药物之间错综复杂的相互作用,阐明了不同区域和性别在反应性上的差异。我们的研究结果强调了在神经结构中识别脆弱性的重要性,并强调了仔细监测阿片类药物的使用以保持抗逆转录病毒疗法疗效的必要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Examining the effects of the HIV-1 protein Tat and morphine on antiretroviral accumulation and distribution within the brain

Examining the effects of the HIV-1 protein Tat and morphine on antiretroviral accumulation and distribution within the brain

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, neuro-acquired HIV (neuroHIV) remains a significant problem and approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND). Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, neuronal injury and synaptodendritic culling, viral replication, and potentially altering antiretroviral concentrations within the brain. The present study examined the effects of HIV and morphine co-exposure on the accumulation and spatial distribution of antiretroviral drugs across multiple regions within the brain in an HIV-1 Tat transgenic mouse model by using infrared-matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI). Morphine exposure uniquely decreased antiretroviral concentrations in anterior cerebral (primary motor and somatosensory) cortices, corpus collosum (anterior forceps), caudoputamen, nucleus accumbens, and posterior regions including the hippocampus, corpus callosum (main body), cerebral cortex (somatosensory and auditory cortices), thalamus, and hypothalamus. Interestingly, male mice experienced greater morphine-associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in antiretroviral concentrations were linked with inflammation in astroglia, assessed through the measurement of astroglial activation using glial fibrillary acidic protein (GFAP) as a marker. Alterations in antiretroviral concentrations co-registering with areas of astroglial activation exhibited sex-specific treatment differences. This study highlights the intricate interplay between HIV, opioids, and antiretroviral drugs within the CNS, elucidating distinct regional and sex variations in responsiveness. Our findings emphasize the identification of vulnerabilities within the neural landscape and underscore the necessity of carefully monitoring opioid use to maintain the efficacy of antiretroviral therapies.

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来源期刊
Cts-Clinical and Translational Science
Cts-Clinical and Translational Science 医学-医学:研究与实验
CiteScore
6.70
自引率
2.60%
发文量
234
审稿时长
6-12 weeks
期刊介绍: Clinical and Translational Science (CTS), an official journal of the American Society for Clinical Pharmacology and Therapeutics, highlights original translational medicine research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease. Translational medicine is a multi-faceted discipline with a focus on translational therapeutics. In a broad sense, translational medicine bridges across the discovery, development, regulation, and utilization spectrum. Research may appear as Full Articles, Brief Reports, Commentaries, Phase Forwards (clinical trials), Reviews, or Tutorials. CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine. Best-in-class methodologies and best practices are also welcomed as Tutorials. These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science. CTS welcomes high quality, scientifically sound, original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of both traditional drugs and innovative modalities.
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