Identification of the Initial Targets of Transmission

识别初始传播目标

• 批准号: 10368220
• 负责人: Thomas Hope
• 金额: $ 91.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368220
• 关键词: AIDS prevention; Adjuvant; Anatomy; Animals; Antigens; Area; Autopsy; Cells; Complex; Environment; Event; Goals; HIV Infections; HIV vaccine; Immune response; Infection; Inflammatory Response; Injectable; Instruction; Intervention; Label; Luciferases; Methodology; Methods; Mucous Membrane; Natural History; PET/CT scan; Pathway interactions; Phase; Physiology; Predisposition; Prevention approach; Principal Investigator; Process; Reporter; SIV; Science; Signal Transduction; Site; Systemic infection; Techniques; Tissues; Tropism; Vagina; Viral; Viremia; Virus; Virus Replication; env Gene Products; innovation; neutralizing antibody; next generation; novel; novel strategies; prevent; preventive intervention; programs; rectal; response; sexual HIV transmission; success; transmission process; vector

Program Director/Principal Investigator (Last, First, Middle): Hope, Thomas J. Recent advances in HIV Prevention science include the demonstration of PreP efficacy of the long acting injectable Cabotegravir and broadly neutralizing antibodies against sensitive strains. Likewise, there have been advances in HIV vaccine science with novel immunogens, adjuvants, and delivery strategies that are increasing the immune responses to the virus and their ability to prevent systemic infection. However, the fine tuning of these preventative interventions and our ability to increase their potency require a better understanding of the mechanisms of HIV sexual transmission. The primary focus of this project has been on 1) developing and optimizing methods allowing the identification of the first cells infected after a mucosal challenge; 2) the characterization of the expanding foci of infection, and 3) the definition of the cascade of events that takes place during the eclipse phase as the virus disseminates before detectable viremia. This project has uniquely impacted and advanced our understanding of the detailed natural history of the virus in the first 4 days after mucosal challenge. This success is a consequence of the innovative approach of beacon-guided necropsy where a signal is generated by the presence of infected cells. The first version of this technique utilized luciferase expressed by a replication defective dual-reporter vector. However, we have developed the next generation of this approach, which uses 64Cu labeled FAB2 probes specific for the SIV envelope protein and PET/CT as next generation beacon-guided necropsy. This approach is highly sensitive and efficient allowing the unbiased identification of multiple foci within the same animal at the whole-body level including the characterization of the interactions of the virus with host innate and inflammatory responses. The study of small foci of infection during the eclipse phase after transmission reveals a complex crosstalk between different infected cells and local tissue environment, which can vary in different areas and tissues within the same animal. This and other observations reveal target cell susceptibility, rather than the “tropism” of the viral envelope, is the key driver of early infection. It is clear that the local anatomy and physiology of virus exposed mucosal tissue has a major impact on the natural history of the virus during the eclipse phase. Through the interrogation of small tissue blocks containing replication foci, we will define the who, where, and when of early mucosal infection, including which cells are generating virus specific alarms and which cells are responding to these alarms. This will be accomplished by incorporating new approaches for the identification of cells migrating into the infected tissue site, restriction of cell mobilization, the disruption of pathways involved in innate and inflammatory responses, and short and long term responses within the infected tissues. Advancing the goals and focus of this project will result in a substantial increase in our understanding of the earliest cascade events in vaginal and rectal transmission. In turn, clarifying this process, and the impact of local anatomy and physiology on virus expansion and dissemination, will clearly advance HIV prevention science. RELEVANCE (See instructions): Developing interventions to prevent HIV infections requires a more complete understanding of how transmission is initiated and progresses to cause systemic infection. The studies proposed here will leverage state-of-the-art methodologies that can identify foci of viral replication that can be defined and characterized to guide optimization of HIV prevention approaches.

计划主任/首席研究员（最后，第一，中间）：希望，托马斯·J。 艾滋病毒预防科学的最新进展包括表现出长期表现的准备效率 可注射的Cabotegravir和针对敏感菌株的抗体广泛中和。同样，也有 我们是艾滋病毒疫苗科学的进步 增加对病毒的免疫反应及其预防全身感染的能力。但是， 对这些预防性干预措施的微调和我们提高其效力的能力需要更好 了解HIV性传播机制。该项目的主要重点是 1）开发和优化方法，允许鉴定在 粘膜挑战； 2）感染局部扩展焦点的表征，3） 随着病毒的传播，在日食期间发生的事件级联 病毒血症。该项目唯一影响并提出了我们对详细自然历史的理解 在粘膜挑战后的前4天，病毒的病毒。这种成功是创新的结果 信号引导的尸检的方法，其中信号是由受感染细胞的存在产生的。这 该技术的第一个版本利用了荧光素酶，由复制有缺陷的双重载体向量表示。 但是，我们已经开发了下一代这种方法，该方法使用了64cu标有fab2问题的方法 特定于SIV包膜蛋白和PET/CT作为下一代信标引导的尸检。这 方法是高度敏感和有效的，允许对多个焦点的公正识别 在整个体内的同一动物，包括病毒与宿主相互作用的表征 先天和炎症反应。在日食阶段的小焦点感染的研究 传播揭示了不同感染细胞与局部组织环境之间的复杂串扰， 在同一动物内的不同地区和组织中可能会有所不同。这个和其他观察结果揭示了 靶细胞敏感性，而不是病毒包膜的“端主”是早期感染的关键驱动力。它 很明显，病毒暴露的粘膜组织的局部解剖学和生理学对 日食期间病毒的自然历史。通过询问小组织块 包含复制灶，我们将定义早期粘膜感染的人，何时何地，包括 哪些细胞正在生成病毒特定警报，哪些细胞对这些警报有响应。这会 可以通过合并新方法来识别迁移到感染的细胞 组织部位，细胞动员的限制，涉及先天和炎症的途径的破坏 反应以及感染组织中的短期和长期反应。促进目标并集中精力 这个项目将导致我们对最早的级联事件的理解大幅增长 阴道和直肠传播。反过来，阐明了这一过程，以及局部解剖学和 关于扩张和传播的生理学，将明显提高HIV预防科学。 相关性（请参阅说明）： 制定干预措施以防止艾滋病毒感染，需要对 开始传播并进展以引起全身感染。这里提出的研究将 利用可以识别可以定义的病毒复制焦点的最先进的方法论学，并 特征是指导预防艾滋病毒预防方法的优化。