Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat
Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat
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DOI：
10.1128/jvi.01484-15
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发表时间：
2015-10-01
影响因子：
5.4
通讯作者：
Lichterfeld, Mathias
中科院分区：
文献类型：
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作者：
Olesen, Rikke;Vigano, Selena;Lichterfeld, Mathias
组蛋白去乙酰化酶抑制剂（HDACi）对休眠HIV-1前病毒的药物再激活代表了一种可能的策略，可减少接受抑制性联合抗逆转录病毒治疗（cART）的个体中HIV-1感染细胞的储存。然而，这种潜伏期逆转剂对病毒储库大小的影响可能受到宿主免疫应答的影响。在这里，我们分析了在一项涉及15名cART治疗的HIV-1感染患者的人体临床试验中，与强效HDACi帕比司他治疗期间前病毒HIV-1 DNA水平变化相关的免疫因素。我们观察到，在帕比司他治疗期间，HIV-1特异性CD8 T细胞应答的幅度、宽度和细胞因子分泌谱与CD4 T细胞中HIV-1 DNA水平的变化无关。相反，整个研究期间，CD3（-）CD56（+）总NK细胞和CD16（+）CD56（dim）NK细胞的比例与HIV-1 DNA水平呈负相关，帕比司他治疗期间HIV-1 DNA水平的变化与CD69（+）NK细胞的相应变化呈负相关。潜伏期逆转治疗期间HIV-1 DNA水平的降低也与浆细胞样树突状细胞的比例、干扰素刺激基因的不同表达模式以及IL 28 B CC基因型的表达有关。总之，这些数据表明，先天免疫活性可以严重调节潜伏逆转剂对病毒库的影响，并可能代表未来的免疫干预HIV-1根除studies. IMPORTANCE目标目前可用的抗逆转录病毒药物是非常有效的抑制HIV-1复制，但病毒持续存在，尽管治疗，在一个潜伏的形式，不积极表达HIV-1基因产物。一种消除这些细胞的方法，俗称"休克和杀伤"策略，集中于使用潜伏逆转剂，诱导潜伏感染细胞中的活性病毒基因表达，然后免疫介导的杀伤。Panobinostat是一种组蛋白去乙酰化酶抑制剂，在最近的一项试点临床试验中显示出逆转HIV-1潜伏期的有效活性，并降低了一部分患者的HIV-1 DNA水平。有趣的是，我们发现先天免疫因子，如自然杀伤细胞，浆细胞样树突状细胞和干扰素刺激基因的表达模式，与帕比司他治疗期间HIV-1 DNA水平的下降最密切相关。这些数据表明，先天免疫活性可能在减少HIV-1感染细胞的残留库中发挥重要作用。
The pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1-infected cells in individuals treated with suppressive combination antiretroviral therapy (cART). However, the effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed the immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1-infected patients. We observed that the magnitude, breadth, and cytokine secretion profile of HIV-1-specific CD8 T cell responses were unrelated to changes in HIV-1 DNA levels in CD4 T cells during panobinostat treatment. In contrast, the proportions of CD3(-) CD56(+) total NK cells and CD16(+) CD56(dim) NK cells were inversely correlated with HIV-1 DNA levels throughout the study, and changes in HIV-1 DNA levels during panobinostat treatment were negatively associated with the corresponding changes in CD69(+) NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to the proportions of plasmacytoid dendritic cells, to distinct expression patterns of interferon-stimulated genes, and to the expression of the IL28B CC genotype. Together, these data suggest that innate immune activity can critically modulate the effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies.IMPORTANCECurrently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists, despite treatment, in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed the "shock-and-kill" strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial and reduced HIV-1 DNA levels in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells, and the expression patterns of interferon-stimulated genes, were most closely linked to a decline in the HIV-1 DNA level during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1-infected cells.