A highly intensified ART regimen induces long-term viral suppression and restriction of the viral reservoir in a simian AIDS model.
A highly intensified ART regimen induces long-term viral suppression and restriction of the viral reservoir in a simian AIDS model.
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DOI：
10.1371/journal.ppat.1002774
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Savarino A
中科院分区：
文献类型：
--
作者：
Shytaj IL;Norelli S;Chirullo B;Della Corte A;Collins M;Yalley-Ogunro J;Greenhouse J;Iraci N;Acosta EP;Barreca ML;Lewis MG;Savarino A
抗逆转录病毒治疗期间稳定抑制的病毒血症对于建立可靠的艾滋病毒/艾滋病猿类模型至关重要。我们在sivmac251感染的恒河猴体内测试了一种多药抗逆转录病毒治疗（高度强化抗逆转录病毒治疗）在广泛病毒血症条件下（103-107病毒RNA拷贝/mL）的疗效，以及它对病毒库的影响。11只艾滋病前期的猕猴接受了多药联合治疗（高度强化的抗逆转录病毒治疗），包括两种核苷型/核苷型逆转录酶抑制剂（恩曲他滨和替诺福韦）、一种整合酶抑制剂（雷替格拉韦）、一种蛋白酶抑制剂（利托那韦增强的darunavir）和CCR5阻滞剂马拉维roc。在开始高强度抗逆转录病毒治疗后，所有动物的病毒载量都稳定地低于检测极限（即<40 RNA拷贝/mL）。通过将检测灵敏度提高到3rna拷贝/mL，所有受试者的病毒载量仍低于检测极限。重要的是，在随访结束时，所有动物的pbmc和直肠活检以及大多数研究对象的淋巴结活检中，病毒DNA的检测结果低于试验检测限（<2拷贝DNA/5*105细胞）。此外，高度强化的抗逆转录病毒治疗降低了体内的中枢/过渡记忆、效应记忆和激活（HLA-DR+）效应记忆CD4+ t细胞，这与这些亚群作为病毒主要细胞亚群的作用一致。最后，在暂停先前的抗病毒库治疗后病毒载量反弹时进行高强度抗逆转录病毒治疗，最终改善了在暂停第二个治疗周期后病毒载量的自发遏制，从而导致在没有抗逆转录病毒治疗的情况下病毒血症的持续抑制。总之，我们首次在猕猴艾滋病模型中发现，高度强化的抗逆转录病毒治疗完全抑制了病毒载量，并可能限制了病毒库，这使其成为测试艾滋病潜在治疗方法的有用平台。旨在寻找治愈艾滋病的新研究需要动物模型对人类抗逆转录病毒药物有反应。然而，很少有抗逆转录病毒药物对猿类病毒具有交叉活性。在这项研究中，我们扩展了对猿猴逆转录病毒SIVmac251有活性的药物库，并表明该病毒可被蛋白酶抑制剂darunavir和CCR5阻滞剂maraviroc抑制。这两种药物与逆转录酶抑制剂替诺福韦和恩曲他滨以及整合酶抑制剂雷替格拉韦联合使用，导致血浆病毒载量延长至低于测定检测极限，并且令人惊讶的是，限制了病毒库，其标志是病毒DNA。然后，我们决定采用这种多药物治疗方案（称为“高度强化抗逆转录病毒疗法”），以提高先前基于金药物金糠蛋白的策略的效力，金糠蛋白最近被证明能够限制体内病毒库。在先前的治疗之后进行短期的高强度抗逆转录病毒治疗，在暂停治疗后，感染得到了显著的自发控制，这可能为在没有抗逆转录病毒治疗的情况下持续抑制病毒血症铺平了道路。这些结果证实了猕猴艾滋病模型的稳健性，它可能是未来人类艾滋病治疗的先锋。
Stably suppressed viremia during ART is essential for establishing reliable simian models for HIV/AIDS. We tested the efficacy of a multidrug ART (highly intensified ART) in a wide range of viremic conditions (103–107 viral RNA copies/mL) in SIVmac251-infected rhesus macaques, and its impact on the viral reservoir. Eleven macaques in the pre-AIDS stage of the disease were treated with a multidrug combination (highly intensified ART) consisting of two nucleosidic/nucleotidic reverse transcriptase inhibitors (emtricitabine and tenofovir), an integrase inhibitor (raltegravir), a protease inhibitor (ritonavir-boosted darunavir) and the CCR5 blocker maraviroc. All animals stably displayed viral loads below the limit of detection of the assay (i.e. <40 RNA copies/mL) after starting highly intensified ART. By increasing the sensitivity of the assay to 3 RNA copies/mL, viral load was still below the limit of detection in all subjects tested. Importantly, viral DNA resulted below the assay detection limit (<2 copies of DNA/5*105 cells) in PBMCs and rectal biopsies of all animals at the end of the follow-up, and in lymph node biopsies from the majority of the study subjects. Moreover, highly intensified ART decreased central/transitional memory, effector memory and activated (HLA-DR+) effector memory CD4+ T-cells in vivo, in line with the role of these subsets as the main cell subpopulations harbouring the virus. Finally, treatment with highly intensified ART at viral load rebound following suspension of a previous anti-reservoir therapy eventually improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART. In conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for AIDS. Novel research aimed at finding a cure for AIDS requires animal models responding to human antiretroviral drugs. However, there have been few antiretrovirals cross-active against the simian viruses. In this study, we expanded the arsenal of drugs active against the simian retrovirus SIVmac251 and showed that this virus is inhibited by the protease inhibitor, darunavir, and the CCR5 blocker, maraviroc. Administration of these two drugs in combination with the reverse transcriptase inhibitors, tenofovir and emtricitabine, and the integrase inhibitor, raltegravir, resulted in prolonged plasma viral loads below assay detection limits, and, surprisingly, restricted the viral reservoir, a marker of which is viral DNA. We then decided to employ this multidrug regimen (termed “highly intensified ART”) in order to increase the potency of a previous strategy based on the gold drug auranofin, which recently proved able to restrict the viral reservoir in vivo. A short course of highly intensified ART following the previous treatment resulted, upon therapy suspension, in a remarkably spontaneous control of the infection, that may pave the way to a persistent suppression of viremia in the absence of ART. These results corroborate the robustness of the macaque AIDS model as a vanguard for potentially future treatments for HIV in humans.
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影响因子：
3.3
作者：
Groot F;van Capel TM;Schuitemaker J;Berkhout B;de Jong EC
通讯作者：
de Jong EC
影响因子：
17.1
作者：
Bacchetti P;Deeks SG;McCune JM
通讯作者：
McCune JM
DOI：
10.1073/pnas.0707449104
发表时间：
2007-11-27
影响因子：
11.1
作者：
Chen, Hannah Yuan;Di Mascio, Michele;Zhang, Linqi
通讯作者：
Zhang, Linqi
影响因子：
5.4
作者：
Gordon, Shari N.;Weissman, Anna R.;Franchini, Genoveffa
通讯作者：
Franchini, Genoveffa
影响因子：
9.9
作者：
Ellis, RJ;Gamst, AC;McCutchan, JA
通讯作者：
McCutchan, JA