SIV cervicovaginal transmission dynamics

项目摘要 这项研究的目的是描述SIV从宫颈阴道传播的动力学 (CV)暴露于建立的全身性感染。这一目标将通过发展数学 这些模型的动机和验证来自基尔实验室的突破性观察和数据， 这是第一次，在非人类中可辨别但表型相同的SIV克隆的组织水平动力学 在CV暴露于病毒后的灵长类动物（NHP）模型中。以前在HIV-1传播方面的工作表明， 一个大的，往往是不同的感染接种物，只有一个小的创始人人口是成功地建立 全身感染艾滋病毒最容易在日食阶段早期受到干预，即，期间 宿主暴露于病毒和可检测的病毒血症。但日食阶段的动力学是复杂的，不能直接 在人类身上进行了研究，但仍然知之甚少。在这项拟议的研究中开发的模型将用于 根据来自Keele实验室的组织水平SIV数据来表征蚀相。数学模型 将分阶段开发，反复完善描述感染的模型，从病毒/细胞相互作用的网站 CV组织中的暴露、病毒向淋巴组织的传播和全身感染的建立。 重要的是，虽然模型的复杂性增加，但每个子模型都将回答重要的特定问题。为 例如，体内感染细胞爆发大小将被量化，以解决“超级传播者”假设， 最初的感染动力学是由一小部分感染细胞驱动的，这些细胞产生的病毒明显更多 比平均水平。这将导致CV组织中基本繁殖数R 0的估计，其为 目前未知。间接证据表明，表型如干扰素（IFN）抗性和高 复制能力可能有利于创始病毒的选择。目前没有实验 存在直接评估这些表型对遗传性的相对贡献的装置或设计。在 因此，将使用计算机竞争实验来检验以下假设： CV感染选择具有快速复制动力学的病毒变体，但随着IFN应答变得更强， 和靶细胞数量增加，选择压力转移到有利于IFN抗性变体。 由于NHP模型经常被用来指导有关艾滋病毒的公共卫生措施，因此直接 由于无法获得观察结果，所提出的SIV感染最早期事件的改进表征将 促进制定更好的艾滋病毒预防措施，如新的妇女预防战略。 这个跨学科的建议桥梁领先的专业知识，在理论和实验生物学发展 这一理论将从根本上改变目前对HIV CV传播的理解。

PROJECT SUMMARY The goal of this proposed study is to delineate the dynamics of SIV transmission from cervicovaginal (CV) exposure to establishment of systemic infection. This goal will be accomplished by developing mathematical models motivated and validated by ground-breaking observations and data from the Keele Lab that show, for the first time, tissue-level dynamics of discriminable but phenotypically identical SIV clones in a nonhuman primate (NHP) model following CV exposure to the virus. Previous work in HIV-1 transmission shows that from a large, and often diverse infecting inoculum, only a small founder population is successful in establishing systemic infection. HIV are most vulnerable to interventions early in the eclipse phase, i.e., the period between host exposure to virus and detectable viremia. But eclipse-phase dynamics are complex, cannot be directly studied in humans, and remain poorly understood. The models developed in this proposed study will be used to characterize the eclipse phase based on the tissue-level SIV data from the Keele Lab. The mathematical model will be developed in stages, iteratively refining models describing infection, from virus/cell interaction at the site of exposure in CV tissue, to dissemination of virus to lymphoid tissue and establishment of systemic infection. Importantly, while models increase in complexity, each sub-model will answer important specific questions. For example, the infected cell burst size in vivo will be quantified to address the “superspreader” hypothesis, that initial infection dynamics are driven by the small fraction of infected cells that produce significantly more virus than the average. This will lead to an estimation of the basic reproduction number R0 in CV tissues, which is currently unknown. Indirect evidence suggests that phenotypes such as interferon (IFN) resistance and high replicative capacity may be advantageous for selection of founder virus. However no current experimental apparatus or design exists to directly assess the relative contribution of these phenotypes to transmissibility. In silico competition experiments will therefore be used to test the hypothesis that the sparsity of target cells in early CV infection selects for virus variants with fast replication kinetics, but that as IFN responses become stronger and target cells numbers increase, selection pressure shifts to favor IFN resistant variants. Since NHP models are often relied upon to guide public health measures regarding HIV when direct observations are unavailable, the improved characterization of the earliest events of SIV infection proposed will facilitate the development of better HIV prevention measures, such as novel prophylactic strategies for women. This interdisciplinary proposal bridges leading expertise in theoretical and experimental biology to develop theory that will fundamentally transform current understanding of HIV CV transmission.