免疫治疗的细胞因子可以激活免疫细胞对抗癌症和慢性感染。N-803是一种IL-15超激动剂，可扩增CD8+ T细胞并增加其细胞毒性。N-803还暂时减少了某些被感染为HIV模型的类人灵长类动物的病毒载量。然而，并非所有被感染为HIV模型的SIV样本都观察到病毒抑制作用，这可能取决于预处理病毒载量及其对CD8+ T细胞的相应影响。在现有N-803治疗SIV的机制数学模型的基础上，我们发展了一个包括抗原、炎症和N-803激活SIV特异和非特异的CD8+ T细胞的模型。模型还包括一种调节性反应，抑制CD8+ T细胞的增殖和功能，代表免疫检查点分子和免疫抑制细胞的影响。我们同时校准了两个单独的SIV样本的模型。第一个样本在治疗前的病毒载量较低（≈3-4 log病毒RNA拷贝当量（CEQ）/mL），N-803治疗暂时抑制了病毒载量。第二个样本在治疗前的病毒载量较高（≈5-7 log CEQ/mL），N-803未能持续抑制病毒载量。根据不同的预处理病毒载量和相应对CD8+ T细胞的调节性抑制水平（即模型的初始条件），数学模型可以重现这两个样本的病毒和CD8+ T细胞动力学。我们的预测结果通过这些和其他SIV样本的附加数据得到了验证。尽管两个样本的模拟中都有高活化的SIV特异性CD8+ T细胞的数量，但由于细胞毒性的抑制增加，高病毒载量样本中无法实现病毒抑制。因此，我们通过数学方式展示了预处理病毒载量如何影响免疫治疗的有效性，强调了可能最大化疗效和改善治疗结果的体内条件和联合治疗。版权所有：© 2023 Cody等。本文是根据创作共用许可证进行的，允许在任何媒体中无限制使用、分发和复制，前提是保留原作者和原出处的署名。

Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment (≈3-4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads (≈5-7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes.Copyright: © 2023 Cody et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.