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AZD5582 联合 SIV 特异性抗体可减少抗逆转录病毒治疗抑制的猕猴淋巴结中的病毒储存库。

AZD5582 plus SIV-specific antibodies reduce lymph node viral reservoirs in antiretroviral therapy-suppressed macaques.

机构信息

Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.

Emory National Primate Research Center, Emory University, Atlanta, GA, USA.

出版信息

Nat Med. 2023 Oct;29(10):2535-2546. doi: 10.1038/s41591-023-02570-7. Epub 2023 Oct 2.

DOI:10.1038/s41591-023-02570-7
PMID:37783968
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10579098/
Abstract

The main barrier to HIV cure is a persistent reservoir of latently infected CD4 T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir. In this study, we investigated the effects of AZD5582 in combination with four SIV Env-specific Rhesus monoclonal antibodies (RhmAbs) ± N-803 (an IL-15 superagonist) in SIV-infected, ART-suppressed rhesus macaques. Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4 T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure.

摘要

HIV 治愈的主要障碍是潜伏感染的 CD4 T 细胞中存在持续的病毒储存库，这些细胞携带具有复制能力的前病毒，在抗逆转录病毒治疗 (ART) 中断后会引发病毒血症反弹。一种针对该储存库的主要方法是使用能够重新激活潜伏 HIV 前病毒的药物，然后通过免疫效应细胞和免疫疗法直接清除表达诱导性病毒抗原的细胞。我们之前曾表明，凋亡蛋白抑制剂拮抗剂 AZD5582 和第二线粒体衍生的半胱天冬酶激活剂 (IAPi/SMACm) 的模拟物可诱导全身性 HIV/SIV 潜伏逆转，但不会减少病毒储存库的大小。在这项研究中，我们研究了 AZD5582 与四种 SIV Env 特异性恒河猴单克隆抗体 (RhmAbs) 联合使用（±N-803，一种 IL-15 超级激动剂）在 SIV 感染、ART 抑制的恒河猴中的效果。在这里，我们证实了 AZD5582 诱导 SIV 重新激活的功效，证明了当 AZD5582 与 N-803 联合使用时，潜伏逆转得到增强，并显示出在接受 AZD5582+RhmAbs 治疗的猕猴的淋巴结源性 CD4 T 细胞中总 SIV-DNA 和具有复制能力的 SIV-DNA 减少。进一步探索这种治疗方法可能有助于实现 HIV 治愈的目标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/f2f2830673c8/41591_2023_2570_Fig12_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/f2f2830673c8/41591_2023_2570_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/ffc3b28d0db1/41591_2023_2570_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/59268fa910b8/41591_2023_2570_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/8d5427bb3fbd/41591_2023_2570_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/bf1b87fa8497/41591_2023_2570_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/c02ed5ba8413/41591_2023_2570_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/068c17731d33/41591_2023_2570_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/12bc787ab5dd/41591_2023_2570_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/00384e7cc615/41591_2023_2570_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/27be747fb425/41591_2023_2570_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/059e26074636/41591_2023_2570_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/4efb33ba19a0/41591_2023_2570_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ace0/10579098/f2f2830673c8/41591_2023_2570_Fig12_ESM.jpg

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[7]
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[8]
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本文引用的文献

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J Virol. 2020-10-14

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