SIV cervicovaginal transmission dynamics

项目总结 这项拟议的研究的目标是描绘SIV从宫颈阴道传播的动力学。 (Cv)暴露于建立的系统性感染。这一目标将通过发展数学 由突破性的观测和来自Keele实验室的数据激励和验证的模型表明， 首次在非人类中发现可区分但表型相同的SIV克隆的组织水平动力学 暴露于病毒后的灵长类动物(NHP)模型。先前关于HIV-1传播的研究表明，从 一个大的，而且往往是多样化的感染接种，只有一小部分创始人群体成功地建立了 全身感染。艾滋病毒最容易受到日食阶段早期干预的影响，即 宿主暴露于病毒和可检测到的病毒血症。但日食位相动力学是复杂的，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数据描述日食阶段。数学模型 将分阶段开发，反复完善描述感染的模型，从现场的病毒/细胞相互作用 暴露在心血管组织中、病毒传播到淋巴组织和建立全身性感染。 重要的是，虽然模型的复杂性增加了，但每个子模型都将回答重要的特定问题。为 例如，体内受感染的细胞突发大小将被量化，以解决“超级传播者”假说，即 最初的感染动力是由一小部分产生显著更多病毒的感染细胞驱动的 比平均水平要高。这将导致对CV组织中的基本繁殖次数R0的估计，即 目前尚不清楚。间接证据表明，干扰素(干扰素)耐药和高 复制能力可能有利于方正病毒的选择。然而，目前没有进行实验 存在直接评估这些表型对传播率的相对贡献的装置或设计。在……里面 因此，电子竞争实验将被用来检验这样的假设，即早期靶细胞的稀疏性 CV感染选择复制速度快的病毒变体，但随着干扰素反应变得更强 靶细胞数量增加，选择压力转向对干扰素耐药的变异体。 由于国家卫生规划模型经常被依赖于指导有关艾滋病毒的公共卫生措施，当 没有观察到，对SIV感染最早事件的改进描述建议将 促进制定更好的艾滋病毒预防措施，例如针对妇女的新的预防战略。 这一跨学科的建议将理论生物学和实验生物学的领先专业知识联系起来，以开发 这一理论将从根本上改变目前对艾滋病病毒传播的理解。

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.