Mutational pathways in early HIV infection: novel guide to immunologic analyses

早期 HIV 感染的突变途径：免疫学分析新指南

• 批准号: 7927933
• 负责人: VLADIMIR A NOVITSKY
• 金额: $ 23.95万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7927933
• 关键词: Accounting; Address; Antigens; Appearance; Asses; Biological Assay; Complement; Complex; Development; Disease Outcome; Equation; Equilibrium; Event; Evolution; Future; Gagging; Genome; HIV; HIV Infections; HIV-1; HIV-1 vaccine; Immune; Immune response; Immunologics; Infection; Knowledge; Letters; Link; Maps; Methods; Mutation; Pathogenesis; Pathway interactions; Pattern; Pennsylvania; Phase; Play; Prevention strategy; Role; Sampling; Series; Side; T cell response; Time; Time Study; Translating; Universities; Vaccine Design; Viral; Virus; Virus Diseases; base; design; fitness; improved; in vivo; novel; novel strategies; pressure; prospective; public health relevance; virus host interaction

DESCRIPTION (provided by applicant): The lack of understanding of the correlates of protection may lie, at least partially, in the fact that historically virus-host interactions have not been studied interactively, but rather by focusing on a single side of the equation. The hypothesis of this study is built on the assumptions that viral mutational pathways in natural HIV-1 infection are restricted by the viral in vivo evolutionary space, and that viral evolutionary space within a given host is confined by a dynamic balance between immune responses and viral fitness. We hypothesize that comprehensive assessment of viral mutational pathways in the early phase of HIV-1 infection may help in formulating specific immunologic questions leading to thorough interactive analysis of virus-specific immune responses, and is likely to result in better understanding of HIV pathogenesis. Applying a novel approach of direct mapping of Gag mutations along the time line of HIV-1 infection, patterns of viral dynamics will be assessed with a particular focus on timing and relationships between different types of viral mutations, and will be translated to a series of specific immunologic hypotheses revealing the mechanisms of virus-host interactions. Aim 1: To identify and characterize HIV-1C Gag mutational pathways. To map time of appearance, dominance, and completeness (or transiency/loss) of viral mutations in HIV-1C Gag by utilizing prospective sample sets with estimated time of seroconversion and applying single-genome amplification/sequencing and ultra-deep sequencing (in a subset). Aim 2: To design a series of immunologically relevant hypotheses focusing on the dynamic interactions between immune responses and viral mutational pathways. The specific immunologic questions will be addressed based on actual mutational pathways, and therefore, will improve existing methods of assessing virus-specific T cell responses in primary HIV infection, and will help to explore correlates and mechanisms of immune protection in future studies. The proposed study will reveal early evolutionary dynamics of host-virus interactions, and will likely enable better immunogen design. PUBLIC HEALTH RELEVANCE: The lack of understanding of the correlates of protection may lie, at least partially, in the fact that historically virus-host interactions have not been studied interactively, but rather by focusing on a single side of the equation. The study will apply a novel approach of direct mapping of Gag mutations along the time line of HIV-1 infection, and will asses patterns of viral dynamics with a particular focus on timing and relationships between different types of viral mutations. Results will be translated to a series of specific immunologic hypotheses revealing the mechanisms of virus-host interactions.

描述（由申请人提供）：缺乏对保护相关性的理解至少在某种程度上可能存在，这是因为历史上没有进行交互性研究，而是通过专注于方程式的单一侧面进行了研究。这项研究的假设建立在自然HIV-1感染中病毒突变途径的假设上，受体内进化空间的限制，并且给定宿主内的病毒进化空间受到免疫反应和病毒适应性之间的动态平衡的限制。我们假设在HIV-1感染的早期对病毒突变途径的全面评估可能有助于制定特定的免疫学问题，从而对病毒特异性免疫反应进行彻底的互动分析，并可能会更好地理解HIV的发病机理。将在HIV-1感染的时间线上直接映射GAG突变的新方法，将评估病毒动力学的模式，特别关注不同类型的病毒突变之间的时间和关系，并将转化为一系列特定的免疫学假设，揭示了病毒 - 霍斯特相互作用的机制。目的1：识别和表征HIV-1C插科打突变途径。通过利用具有估计的血清转化时间的前瞻性样品集并应用单基因组扩增/测序和超深测序（在子集中），通过利用前瞻性样品集来绘制HIV-1C GAG中病毒突变的外观，优势和完整性（或易于损失）。目标2：设计一系列与免疫相关的假设，重点是免疫反应与病毒突变途径之间的动态相互作用。将根据实际的突变途径解决特定的免疫问题，因此，将改善评估原发性HIV感染中病毒特异性T细胞反应的现有方法，并将有助于探索未来研究中免疫保护的相关性和机制。拟议的研究将揭示宿主病毒相互作用的早期进化动力学，并可能会实现更好的免疫原设计。 公共卫生相关性：缺乏对保护的相关性的理解至少在某种程度上可能存在，这是因为历史上没有进行互动研究，而是通过专注于方程式的一面来进行研究。这项研究将采用新型的方法，即在HIV-1感染的时间线上直接映射GAG突变，并将评估病毒动力学的模式，特别关注不同类型的病毒突变之间的时间和关系。结果将转化为一系列特定的免疫学假设，揭示了病毒宿主相互作用的机制。