Mathematical modeling of N-803 treatment in SIV-infected non-human primates.
Mathematical modeling of N-803 treatment in SIV-infected non-human primates.
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DOI：
10.1371/journal.pcbi.1009204
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发表时间：
2021-07
影响因子：
4.3
通讯作者：
Pienaar E
中科院分区：
文献类型：
--
作者：
Cody JW;Ellis-Connell AL;O'Connor SL;Pienaar E
免疫调节药物可能有助于人类免疫缺陷病毒（HIV）的功能性治疗。白细胞介素-15（IL-15）促进CD 8 + T细胞和自然杀伤（NK）细胞群的扩增和活化。在一项研究中，IL-15超激动剂N-803抑制了先前接受过猴免疫缺陷病毒（SIV）疫苗接种的非人灵长类动物（NHP）中的SIV。然而，病毒抑制随着N-803持续治疗而减弱，在长时间治疗中断后部分恢复。虽然有证据表明同时存在药物耐受性、免疫调节和病毒逃逸，但这些机制对观察到的病毒动力学的相对贡献尚未量化。在这里，我们利用N-803治疗SIV感染猕猴的数学模型来估计这三个关键机制对治疗结果的贡献：1）药物耐受性，2）免疫调节和3）病毒逃逸。我们根据上述NHP研究中的病毒和淋巴细胞反应校准了我们的模型。我们的模型跟踪具有N-803依赖性增殖和激活的CD 8 + T细胞和NK细胞群体，以及响应这些免疫细胞群体的病毒动力学。我们比较了数学模型与不同的组合的三个关键机制的基础上赤池信息准则和重要的定性特征的NHP数据。两个最小模型能够重现观察到的SIV对N-803的反应。在这两种模型中，免疫调节强烈降低了细胞毒性细胞活化，使病毒反弹。长期药物耐受性或病毒逃逸（或其某种组合）可以解释N-803治疗长时间中断期间病毒动力学的变化。模型的理论探索表明，较低频率的N-803给药和同时的免疫调节阻断（例如PD-L1抑制）可能会改善N-803的疗效。然而，N-803可能需要与其他免疫疗法联合使用，以抑制病毒从CD 8 + T细胞应答中逃逸。我们的机制模型将告知这种治疗设计和指导未来的研究。免疫治疗可能是人类免疫缺陷病毒（HIV）功能性治疗的关键组成部分。N-803是一种免疫抑制剂，可激活免疫系统的抗原特异性CD 8 + T细胞。这些CD 8 + T细胞消除HIV感染的细胞，以限制感染在体内的传播。在一项研究中，N-803减少了感染猿猴免疫缺陷病毒（HIV的一种类似物）的猕猴的血浆病毒血症。在这里，我们使用数学模型来分析本研究的数据，以更好地了解N-803治疗对免疫系统的影响。我们的模型表明，抑制信号可能会逆转N-803的刺激作用。结果还表明，对N-803的耐受性可以在CD 8 + T细胞本身内建立，并且治疗可能选择不被CD 8 + T细胞靶向的病毒株。我们的模型预测，如果剂量之间的时间增加或抑制信号被其他药物阻断，N-803治疗可能会更有效。此外，N-803可能需要与其他免疫疗法结合，以靶向病毒，否则会逃避CD 8 + T细胞。
Immunomodulatory drugs could contribute to a functional cure for Human Immunodeficiency Virus (HIV). Interleukin-15 (IL-15) promotes expansion and activation of CD8+ T cell and natural killer (NK) cell populations. In one study, an IL-15 superagonist, N-803, suppressed Simian Immunodeficiency Virus (SIV) in non-human primates (NHPs) who had received prior SIV vaccination. However, viral suppression attenuated with continued N-803 treatment, partially returning after long treatment interruption. While there is evidence of concurrent drug tolerance, immune regulation, and viral escape, the relative contributions of these mechanisms to the observed viral dynamics have not been quantified. Here, we utilize mathematical models of N-803 treatment in SIV-infected macaques to estimate contributions of these three key mechanisms to treatment outcomes: 1) drug tolerance, 2) immune regulation, and 3) viral escape. We calibrated our model to viral and lymphocyte responses from the above-mentioned NHP study. Our models track CD8+ T cell and NK cell populations with N-803-dependent proliferation and activation, as well as viral dynamics in response to these immune cell populations. We compared mathematical models with different combinations of the three key mechanisms based on Akaike Information Criterion and important qualitative features of the NHP data. Two minimal models were capable of reproducing the observed SIV response to N-803. In both models, immune regulation strongly reduced cytotoxic cell activation to enable viral rebound. Either long-term drug tolerance or viral escape (or some combination thereof) could account for changes to viral dynamics across long breaks in N-803 treatment. Theoretical explorations with the models showed that less-frequent N-803 dosing and concurrent immune regulation blockade (e.g. PD-L1 inhibition) may improve N-803 efficacy. However, N-803 may need to be combined with other immune therapies to countermand viral escape from the CD8+ T cell response. Our mechanistic model will inform such therapy design and guide future studies. Immune therapy may be a critical component in the functional cure for Human Immunodeficiency Virus (HIV). N-803 is an immunotherapeutic drug that activates antigen-specific CD8+ T cells of the immune system. These CD8+ T cells eliminate HIV-infected cells in order to limit the spread of infection in the body. In one study, N-803 reduced plasma viremia in macaques that were infected with Simian Immunodeficiency Virus, an analog of HIV. Here, we used mathematical models to analyze the data from this study to better understand the effects of N-803 therapy on the immune system. Our models indicated that inhibitory signals may be reversing the stimulatory effect of N-803. Results also suggested the possibilities that tolerance to N-803 could build up within the CD8+ T cells themselves and that the treatment may be selecting for virus strains that are not targeted by CD8+ T cells. Our models predict that N-803 therapy may be made more effective if the time between doses is increased or if inhibitory signals are blocked by an additional drug. Also, N-803 may need to be combined with other immune therapies to target virus that would otherwise evade CD8+ T cells.
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