Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
JCI Insight. 2024 Nov 22;9(22):e185480. doi: 10.1172/jci.insight.185480.
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.
阿片类药物的使用可能会影响 HIV-1 储库及其从潜伏期的逆转。我们研究了 47 名病毒得到抑制的 HIV 感染者（PWH），观察到 HIV-1 潜伏期逆转剂（LRAs）的浓度降低，与未逆转潜伏期的小分子联合使用，可协同增加 HIV-1 体外激活的幅度，而与阿片类药物的使用无关。这种 LRA 增强作用，结合了第二种线粒体衍生的 caspase 激活剂模拟物或低剂量 PKC 激动剂与组蛋白去乙酰化酶抑制剂，产生的未剪接 HIV-1 转录比 PMA 与离子霉素（PMAi）更多，后者是已知的最大 HIV-1 激活剂。LRA 增强作用与更高的组蛋白乙酰化相关，调节表面激活诱导的标志物，并改变 T 细胞产生 TNF-α、IL-2 和 IFN-γ。PWH 中的 HIV-1 储库含有未剪接和多聚腺苷酸化的病毒 mRNA，其比例在静止 CD4+T 细胞中高于总 CD4+T 细胞，并且在 PMAi 暴露下校正为 1:1。我们将经治疗抑制的 HIV-1 感染描述为一种转录效率低下而不是缺失的病毒转录时期。多剪接 HIV-1 转录物和病毒颗粒的产生并不总是随着 LRA 增强作用而增加，这表明存在持续的转录后阻断。LRA 增强作用可以用来探究有效的细胞 HIV-1 潜伏期逆转程序的机制。
