Virus Replication Strategies and the Critical CTL Numbers Required for the Control of Infection

Vaccines that elicit protective cytotoxic T lymphocytes (CTL) may improve on or augment those designed primarily to elicit antibody responses. However, we have little basis for estimating the numbers of CTL required for sterilising immunity at an infection site. To address this we begin with a theoretical estimate obtained from measurements of CTL surveillance rates and the growth rate of a virus. We show how this estimate needs to be modified to account for (i) the dynamics of CTL-infected cell conjugates, and (ii) features of the virus lifecycle in infected cells. We show that provided the inoculum size of the virus is low, the dynamics of CTL-infected cell conjugates can be ignored, but knowledge of virus life-histories is required for estimating critical thresholds of CTL densities. We show that accounting for virus replication strategies increases estimates of the minimum density of CTL required for immunity over those obtained with the canonical model of virus dynamics, and demonstrate that this modeling framework allows us to predict and compare the ability of CTL to control viruses with different life history strategies. As an example we predict that lytic viruses are more difficult to control than budding viruses when net reproduction rates and infected cell lifetimes are controlled for. Further, we use data from acute SIV infection in rhesus macaques to calculate a lower bound on the density of CTL that a vaccine must generate to control infection at the entry site. We propose that critical CTL densities can be better estimated either using quantitative models incorporating virus life histories or with in vivo assays using virus-infected cells rather than peptide-pulsed targets.

能够诱导保护性细胞毒性T淋巴细胞（cytotoxic T lymphocytes, CTL）的疫苗，可对主要旨在诱导抗体应答的疫苗进行优化或补强。然而，目前我们几乎没有依据可用于估算感染部位实现清除性免疫所需的CTL数量。为解决这一问题，我们首先从CTL监测速率与病毒生长速率的测量数据中得到了一项理论估算值。我们阐释了该估算值需如何修正，以兼顾（i）CTL-感染细胞结合物的动态变化，以及（ii）感染细胞内病毒生命周期的特征。研究表明，当病毒接种量较低时，CTL-感染细胞结合物的动态变化可忽略不计，但估算CTL密度的临界阈值时，需掌握病毒的生活史特征。我们发现，相较于经典病毒动力学模型，纳入病毒复制策略的建模会提高免疫所需的最小CTL密度估算值，并证实该建模框架可用于预测和比较CTL对不同生活史策略病毒的控制能力。作为示例，我们预测在净繁殖率与感染细胞寿命可控的前提下，裂解型病毒比出芽型病毒更难被CTL控制。此外，我们利用恒河猴急性猴免疫缺陷病毒（Simian Immunodeficiency Virus, SIV）感染的相关数据，计算出疫苗需诱导的CTL密度下限，以在感染入侵部位实现感染控制。我们提出，相较于采用肽脉冲靶细胞的体内实验，结合病毒生活史的定量模型或使用病毒感染细胞的体内实验，能够更精准地估算临界CTL密度。