Human immunodeficiency virus (HIV-1 or simply HIV) induces a persistent infection, which in the absence of treatment leads to AIDS and death in almost all infected individuals. HIV infection elicits a vigorous immune response starting about 2-3 weeks post infection that can lower the amount of virus in the body, but which cannot eradicate the virus. How HIV establishes a chronic infection in the face of a strong immune response remains poorly understood. It has been shown that HIV is able to rapidly change its proteins via mutation to evade recognition by virus-specific cytotoxic T lymphocytes (CTLs). Typically, an HIV-infected patient will generate 4-12 CTL responses specific for parts of viral proteins called epitopes. Such CTL responses lead to strong selective pressure to change the viral sequences encoding these epitopes so as to avoid CTL recognition. Indeed, the viral population "escapes" from about half of the CTL responses by mutation in the first year. Here we review experimental data on HIV evolution in response to CTL pressure, mathematical models developed to explain this evolution, and highlight problems associated with the data and previous modeling efforts. We show that estimates of the strength of the epitope-specific CTL response depend on the method used to fit models to experimental data and on the assumptions made regarding how mutants are generated during infection. We illustrate that allowing CTL responses to decay over time may improve the fit to experimental data and provides higher estimates of the killing efficacy of HIV-specific CTLs. We also propose a novel method for simultaneously estimating the killing efficacy of multiple CTL populations specific for different epitopes of HIV using stochastic simulations. Lastly, we show that current estimates of the efficacy at which HIV-specific CTLs clear virus-infected cells can be improved by more frequent sampling of viral sequences and by combining data on sequence evolution with experimentally measured CTL dynamics.

中文翻译：

---

HIV 从细胞毒性 T 淋巴细胞反应中逃逸的数学模型

人类免疫缺陷病毒（HIV-1 或简称 HIV）会引起持续感染，如果不进行治疗，几乎所有感染者都会导致 AIDS 和死亡。HIV 感染会在感染后约 2-3 周开始引发强烈的免疫反应，这可以降低体内病毒的数量，但不能根除病毒。面对强烈的免疫反应，艾滋病毒如何建立慢性感染仍然知之甚少。已经表明，HIV 能够通过突变快速改变其蛋白质，以逃避病毒特异性细胞毒性 T 淋巴细胞 (CTL) 的识别。通常，感染 HIV 的患者会产生 4-12 个 CTL 反应，这些反应对称为表位的病毒蛋白部分具有特异性。这种 CTL 反应导致强烈的选择压力来改变编码这些表位的病毒序列，从而避免 CTL 识别。事实上，病毒种群在第一年通过突变从大约一半的 CTL 反应中“逃脱”。在这里，我们回顾了有关 HIV 进化以响应 CTL 压力的实验数据、为解释这种进化而开发的数学模型，并强调了与数据和先前建模工作相关的问题。我们表明，表位特异性 CTL 反应强度的估计取决于用于将模型拟合到实验数据的方法以及关于如何在感染期间产生突变体的假设。我们说明，允许 CTL 反应随时间衰减可能会改善对实验数据的拟合，并提供对 HIV 特异性 CTL 杀伤效力的更高估计。我们还提出了一种新方法，用于使用随机模拟同时估计对 HIV 不同表位特异的多个 CTL 群体的杀伤效力。最后，我们表明，通过更频繁地采样病毒序列并将序列进化数据与实验测量的 CTL 动力学相结合，可以提高当前对 HIV 特异性 CTL 清除病毒感染细胞的功效的估计。