Olesen Rikke, Vigano Selena, Rasmussen Thomas A, Søgaard Ole S, Ouyang Zhengyu, Buzon Maria, Bashirova Arman, Carrington Mary, Palmer Sarah, Brinkmann Christel R, Yu Xu G, Østergaard Lars, Tolstrup Martin, Lichterfeld Mathias
Infectious Disease Division, Aarhus University Hospital, Aarhus, Denmark.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA.
J Virol. 2015 Oct;89(20):10176-89. doi: 10.1128/JVI.01484-15. Epub 2015 Jul 29.
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.
Currently 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.
组蛋白去乙酰化酶抑制剂（HDACi）对潜伏的HIV-1前病毒进行药物性再激活，可能是一种减少接受抑制性联合抗逆转录病毒疗法（cART）治疗的个体中HIV-1感染细胞储存库的策略。然而，这种潜伏逆转剂对病毒储存库大小的影响可能受宿主免疫反应的影响。在此，我们在一项涉及15名接受cART治疗的HIV-1感染患者的人体临床试验中，分析了强效HDACi帕比司他治疗期间与HIV-1前病毒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细胞反应的强度、广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，在整个研究过程中，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，并且帕比司他治疗期间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IL28B 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关键地调节潜伏逆转剂对病毒储存库的影响，并且可能代表未来HIV-1根除研究中免疫治疗干预的一个靶点。
目前可用的抗逆转录病毒药物在抑制HIV-1复制方面非常有效，但尽管进行了治疗，病毒仍以潜伏形式持续存在，不主动表达HIV-1基因产物。一种消除这些细胞的方法，通俗地称为“激活并杀死”策略，侧重于使用潜伏逆转剂，在潜伏感染的细胞中诱导活跃的病毒基因表达，随后进行免疫介导的杀伤。在最近的一项先导性临床试验中，组蛋白去乙酰化酶抑制剂帕比司他在逆转HIV-1潜伏方面表现出强大的活性，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素，如自然杀伤细胞、浆细胞样树突状细胞以及干扰素刺激基因的表达模式，与帕比司他治疗期间HIV-1 DNA水平的下降最为密切相关。这些数据表明先天免疫活性可能在减少HIV-1感染细胞的残余储存库中发挥重要作用。
