HIV-1 潜伏期逆转剂的增强作用不受使用阿片类药物的限制。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-22 DOI:10.1172/jci.insight.185480
Tyler Lilie, Jennifer Bouzy, Archana Asundi, Jessica Taylor, Samantha Roche, Alex Olson, Kendyll Coxen, Heather Corry, Hannah Jordan, Kiera Clayton, Nina Lin, Athe Tsibris
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引用次数: 0

摘要

阿片类药物的使用可能会影响 HIV-1 病毒库及其潜伏期的逆转。我们对 47 名病毒抑制的 HIV 感染者(PWH)进行了研究,观察到低浓度的 HIV-1 潜伏期逆转剂(LRA)与不能逆转潜伏期的小分子药物联合使用,能协同增加体内 HIV-1 再激活的程度,而与使用阿片类药物无关。这种 LRA 促进剂将 Smac 模拟物或低剂量蛋白激酶 C 激动剂与组蛋白去乙酰化酶抑制剂结合在一起,产生的未剪接 HIV-1 转录明显多于 12 肉豆蔻酸 13-乙酸磷脂(PMA)与离子霉素(PMAi),后者是已知的最大 HIV-1 再激活剂。LRA 的增强与组蛋白乙酰化的增加、表面活化诱导标志物的调节以及 T 细胞产生 TNFα、IL-2 和 IFNγ 的改变有关。PWH中的HIV-1贮库含有未剪接和多聚腺苷酸化(polyA)的病毒mRNA,其在静息CD4+ T细胞中的比例大于总CD4+ T细胞,在暴露于PMAi的情况下,两者的比例修正为1:1。我们将经过处理的 HIV-1 感染抑制期描述为病毒转录效率低下而非缺失的时期。多重剪接的 HIV-1 转录本和病毒生产并没有随着 LRA 的增强而持续增加,这表明存在持续的转录后阻断。可以利用 LRA 增强来探究有效的细胞 HIV-1 潜伏逆转程序的机制。
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HIV-1 latency reversal agent boosting is not limited by opioid use.

Opioid use may affect the HIV-1 reservoir and its reversal from latency. We studied 47 virally suppressed people with HIV (PWH) and observed that lower concentration of HIV-1 latency reversal agents (LRAs), used with small molecules that did not reverse latency, synergistically increased the magnitude of HIV-1 reactivation ex vivo, regardless of opioid use. This LRA boosting, which combined a second mitochondria-derived activator of caspases mimetic or low-dose PKC agonist with histone deacetylase inhibitors, generated more unspliced HIV-1 transcription than PMA with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation, modulated surface activation-induced markers, and altered T cell production of TNF-α, IL-2, and IFN-γ. HIV-1 reservoirs in PWH contained unspliced and polyadenylated virus mRNA, the ratios of which were greater in resting than total CD4+ T cells and corrected to 1:1 with PMAi exposure. We characterized treated suppressed HIV-1 infection as a period of inefficient, not absent, virus transcription. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent posttranscriptional block. LRA boosting can be leveraged to probe mechanisms of an effective cellular HIV-1 latency reversal program.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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