Policicchio Benjamin B, Xu Cuiling, Brocca-Cofano Egidio, Raehtz Kevin D, He Tianyu, Ma Dongzhu, Li Hui, Sivanandham Ranjit, Haret-Richter George S, Dunsmore Tammy, Trichel Anita, Mellors John W, Hahn Beatrice H, Shaw George M, Ribeiro Ruy M, Pandrea Ivona, Apetrei Cristian
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS Pathog. 2016 Sep 15;12(9):e1005879. doi: 10.1371/journal.ppat.1005879. eCollection 2016 Sep.
Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the "shock and kill" strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet, ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD) to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to <10 SIV RNA copies/mL with ART, without viral blips. At ART cessation, initial rebound viremia to 106 copies/mL was followed by a decline to < 10 copies/mL, suggesting effective immune control. Three post-treatment controller RMs received three doses of RMD every 35-50 days, followed by in vivo experimental depletion of CD8+ cells using monoclonal antibody M-T807R1. RMD was well-tolerated and resulted in a rapid and massive surge in T cell activation, as well as significant virus rebounds (104 copies/ml) peaking at 5-12 days post-treatment. CD8+ cell depletion resulted in a more robust viral rebound (107 copies/ml) that was controlled upon CD8+ T cell recovery. Our results show that RMD can reactivate SIV in vivo in the setting of post-ART viral control. Comparison of the patterns of virus rebound after RMD administration and CD8+ cell depletion suggested that RMD impact on T cells is only transient and does not irreversibly alter the ability of SIV-specific T cells to control the reactivated virus.
尽管接受了看似有效的抗逆转录病毒治疗（ART），病毒仍持续存在，并且在治疗停止时能够重新引发感染，这使得HIV-1感染者无法得到彻底治愈，需要终身接受ART。在针对这些病毒储存库提出的策略中，“激活并清除”策略的前提是诱导潜伏前病毒的表达[例如使用组蛋白去乙酰化酶抑制剂（HDACis）]，从而通过病毒细胞溶解或免疫清除机制消除受影响的细胞。然而，体外研究报告称，HDACis在重新激活潜伏前病毒方面具有不同的疗效，并且会阻碍免疫功能。我们通过早期和长期给予ART建立了一个非人灵长类动物模型，用于模拟治疗后对猴免疫缺陷病毒（SIV）的控制，并在处于病毒控制状态的恒河猴（RM）中进行体内重新激活实验，评估HDACi罗米地辛（RMD）重新激活SIV的能力以及RMD治疗对SIV特异性T细胞反应的影响。十只RM静脉注射了一个SIVsmmFTq传播奠基者感染性分子克隆。四只RM从感染后65天开始接受常规ART治疗超过9个月。通过ART，SIVsmmFTq血浆病毒血症被有效控制在<10个SIV RNA拷贝/毫升，没有病毒波动。在ART停止时，最初的病毒血症反弹至106拷贝/毫升，随后下降至<10拷贝/毫升，表明有效的免疫控制。三只治疗后处于病毒控制状态的RM每35 - 50天接受三剂RMD，随后使用单克隆抗体M-T807R1在体内实验性清除CD8 +细胞。RMD耐受性良好，并导致T细胞活化迅速大量增加，以及在治疗后5 - 12天出现显著的病毒反弹（104拷贝/毫升）峰值。CD8 +细胞清除导致更强烈的病毒反弹（107拷贝/毫升），在CD8 + T细胞恢复后得到控制。我们的结果表明，在ART后病毒控制的情况下，RMD可以在体内重新激活SIV。RMD给药后和CD8 +细胞清除后病毒反弹模式的比较表明，RMD对T细胞的影响只是短暂的，并且不会不可逆转地改变SIV特异性T细胞控制重新激活病毒的能力。
