In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection.
In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection.
复制标题
DOI：
10.1186/s12977-016-0268-7
复制
发表时间：
2016-05-21
期刊：
影响因子：
3.3
通讯作者：
Garcia JV
中科院分区：
文献类型：
--
作者：
Tsai P;Wu G;Baker CE;Thayer WO;Spagnuolo RA;Sanchez R;Barrett S;Howell B;Margolis D;Hazuda DJ;Archin NM;Garcia JV
静息的CD4+T细胞中的潜伏库是HIV治愈的主要障碍。因此，正在开发潜伏期反转剂，最终目标是破坏潜伏期状态，从而诱导艾滋病毒表达并清除受感染的细胞。组蛋白去乙酰酶抑制剂(HDACi)因其潜在的潜伏期逆转作用而受到广泛关注。在这里，我们研究了临床上相关的HDACi帕诺比妥在体外和体内对HIV潜伏期的影响。我们发现帕诺比妥能诱导人外周血单核细胞中组蛋白乙酰化。此外，我们还发现，在抑制性抗逆转录病毒治疗(ART)中，Panobinostat诱导了HIV RNA的表达，并允许HIV感染患者静息的CD4+T细胞在体外生长具有复制能力的病毒。接下来，我们在BLT人源化小鼠的组织中证明了Panobinostat在体内诱导了全身性组蛋白乙酰化。最后，在HIV感染、ART抑制的BLT小鼠中，我们评估了Panobinostat对全身细胞相关的HIV RNA和DNA水平以及潜伏感染的静止CD4+T细胞的总频率的影响。我们的数据表明，Panobinostat治疗导致组蛋白乙酰化的细胞水平全身性增加，组蛋白乙酰化是体内活性的关键生物标记物。然而，Panobinostat并不影响细胞相关的HIV RNA、HIV DNA或潜伏感染的静息CD4+T细胞的水平。我们已经证明，在BLT人源化小鼠的Panobinostat治疗后，全身性组蛋白乙酰化水平很高；在HIV感染、ART抑制的BLT小鼠中，我们没有观察到细胞相关HIV RNA、HIV DNA或潜伏感染的静止CD4+T细胞水平的可检测变化。这些结果与体外实验中注意到的温和效果一致，并表明联合治疗可能是必要的，以逆转潜伏期和实现清除。动物模型将有助于HIV治愈的进展。
The latent reservoir in resting CD4+ T cells presents a major barrier to HIV cure. Latency-reversing agents are therefore being developed with the ultimate goal of disrupting the latent state, resulting in induction of HIV expression and clearance of infected cells. Histone deacetylase inhibitors (HDACi) have received a significant amount of attention for their potential as latency-reversing agents. Here, we have investigated the in vitro and systemic in vivo effect of panobinostat, a clinically relevant HDACi, on HIV latency. We showed that panobinostat induces histone acetylation in human PBMCs. Further, we showed that panobinostat induced HIV RNA expression and allowed the outgrowth of replication-competent virus ex vivo from resting CD4+ T cells of HIV-infected patients on suppressive antiretroviral therapy (ART). Next, we demonstrated that panobinostat induced systemic histone acetylation in vivo in the tissues of BLT humanized mice. Finally, in HIV-infected, ART-suppressed BLT mice, we evaluated the effect of panobinostat on systemic cell-associated HIV RNA and DNA levels and the total frequency of latently infected resting CD4+ T cells. Our data indicate that panobinostat treatment resulted in systemic increases in cellular levels of histone acetylation, a key biomarker for in vivo activity. However, panobinostat did not affect the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4+ T cells. We have demonstrated robust levels of systemic histone acetylation after panobinostat treatment of BLT humanized mice; and we did not observe a detectable change in the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4+ T cells in HIV-infected, ART-suppressed BLT mice. These results are consistent with the modest effects noted in vitro and suggest that combination therapies may be necessary to reverse latency and enable clearance. Animal models will contribute to the progress towards an HIV cure.