Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques.
Arsenic trioxide-induced apoptosis contributes to suppression of viral reservoir in SIV-infected rhesus macaques.
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DOI：
10.1128/spectrum.00525-23
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发表时间：
2023-09-11
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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潜伏性病毒储库被认为是实现HIV感染功能性治愈的主要障碍。我们以前报道过，三氧化二砷（As 2 O3）联合抗逆转录病毒治疗（ART）可以重新激活病毒库，延缓病毒反弹后，ART中断慢性猴免疫缺陷病毒（SIV）感染的猕猴。在这项研究中，我们进一步研究了As 2 O3的效果独立于ART在慢性SIV感染的猕猴。我们发现，仅As 2 O3治疗显著增加了慢性SIVmac 239感染猕猴的CD 4/CD 8比值，改善了SIV特异性T细胞应答，并重新激活了病毒潜伏期。RNA测序分析显示，As 2 O3处理下调与HIV进入和感染相关的基因的表达水平，而与转录起始、细胞凋亡和宿主限制因子相关的基因的表达水平显著上调。重要的是，我们发现As 2 O3处理特异性地诱导SIV感染的CD 4 + T细胞凋亡。这些结果表明，As 2 O3不仅可以影响病毒的潜伏期，而且可以诱导HIV感染细胞的凋亡，从而阻断旁观者的二次感染。此外，我们研究了该方案在急性SIVmac 239感染猕猴中的治疗潜力，发现As 2 O3 + ART治疗有效地恢复了急性SIV感染猕猴的CD 4 + T细胞计数，延迟了疾病进展，并提高了生存率。总之，这项工作提供了新的见解，开发作为一个组成部分的As 2 O3的“休克和杀死”的策略，对艾滋病毒的功能性治疗。抗逆转录病毒治疗（ART）虽然能有效地抑制艾滋病患者的病毒载量，但由于HIV宿主的存在，它不能在功能上治愈HIV感染。艾滋病毒功能性治愈的策略仍然被高度期望最终结束艾滋病的流行。在此，我们研究了As 2 O3在慢性SIV感染的猕猴中独立于ART的直接作用，并探讨了As 2 O3治疗HIV/SIV感染的潜在机制。同时，我们研究了ART+ As_2O_3对急性SIVmac 239感染猕猴的治疗作用。本研究表明，由于As 2 O3具有潜伏期逆转和诱导凋亡的特性，它有可能被用于“休克和杀死”策略，以抑制HIV/SIV库。
Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the “shock-and-kill” strategy toward HIV functional cure. Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the “shock-and-kill” strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.
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影响因子：
11.1
作者：
Ananworanich, Jintanat;Chomont, Nicolas;Eller, Leigh Ann;Kroon, Eugene;Tovanabutra, Sodsai;Bose, Meera;Nau, Martin;Fletcher, James L. K.;Tipsuk, Somporn;Vandergeeten, Claire;O'Connell, Robert J.;Pinyakorn, Suteeraporn;Michael, Nelson;Phanuphak, Nittaya;Robb, Merlin L.
通讯作者：
Robb, Merlin L.
影响因子：
30.3
作者：
Lusic, Marina;Marini, Bruna;Giacca, Mauro
通讯作者：
Giacca, Mauro
DOI：
10.1073/pnas.96.6.2627
发表时间：
1999-03-16
影响因子：
11.1
作者：
Doucas, V;Tini, M;Evans, RM
通讯作者：
Evans, RM
影响因子：
158.5
作者：
Huetter, Gero;Nowak, Daniel;Thiel, Eckhard
通讯作者：
Thiel, Eckhard
影响因子：
20.3
作者：
Moir, Susan;Buckner, Clarisa M.;Fauci, Anthony S.
通讯作者：
Fauci, Anthony S.