Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Immunol Rev. 2018 Sep;285(1):113-133. doi: 10.1111/imr.12672.
Herpes simplex virus-2 infection is characterized by frequent episodic shedding in the genital tract. Expansion in HSV-2 viral load early during episodes is extremely rapid. However, the virus invariably peaks within 18 hours and is eliminated nearly as quickly. A critical feature of HSV-2 shedding episodes is their heterogeneity. Some episodes peak at 10 HSV DNA copies, last for weeks due to frequent viral re-expansion, and lead to painful ulcers, while others only reach 10 HSV DNA copies and are eliminated within hours and without symptoms. Within single micro-environments of infection, tissue-resident CD8+ T cells (T ) appear to contain infection within a few days. Here, we review components of T biology relevant to immune surveillance between HSV-2 shedding episodes and containment of infection upon detection of HSV-2 cognate antigen. We then describe the use of mathematical models to correlate large spatial gradients in T density with the heterogeneity of observed shedding within a single person. We describe how models have been leveraged for clinical trial simulation, as well as future plans to model the interactions of multiple cellular subtypes within mucosa, predict the mechanism of action of therapeutic vaccines, and describe the dynamics of 3-dimensional infection environment during the natural evolution of an HSV-2 lesion.
单纯疱疹病毒 2 型感染的特征是生殖器部位频繁出现间歇性排毒。在发作早期，HSV-2 病毒载量迅速增加。然而，病毒总是在 18 小时内达到峰值，并迅速被清除。HSV-2 排毒发作的一个关键特征是其异质性。一些发作峰值达到 10 拷贝的 HSV DNA，由于频繁的病毒再扩增而持续数周，并导致疼痛性溃疡，而另一些仅达到 10 拷贝的 HSV DNA，并在数小时内被清除而无症状。在感染的单个微环境中，组织驻留的 CD8+T 细胞（T 细胞）似乎在几天内就将感染控制住了。在这里，我们回顾了与 HSV-2 排毒发作期间免疫监测和检测到 HSV-2 同源抗原后感染控制相关的 T 生物学成分。然后，我们描述了如何使用数学模型将 T 细胞密度的大空间梯度与单个人体中观察到的排毒异质性相关联。我们描述了如何利用模型进行临床试验模拟，以及未来计划对多个细胞亚型在黏膜中的相互作用进行建模，预测治疗性疫苗的作用机制，并描述在 HSV-2 病变的自然演变过程中 3 维感染环境的动力学。
