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可能至少部分地在于，历史上病毒-宿主相互作用没有进行交互式研究，而是集中在等式的一侧。本研究的假设是建立在这样的假设上，即自然HIV-1感染中的病毒突变途径受到病毒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应答和病毒适应性之间的动态平衡的限制。我们假设，在HIV-1感染的早期阶段，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，导致病毒特异性免疫反应的全面互动分析，并可能导致更好地了解HIV的发病机制。应用一种新的方法，沿着HIV-1感染的时间线直接绘制Gag突变，将评估病毒动力学模式，特别关注不同类型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病毒与宿主相互作用的机制。目的1：鉴定和表征HIV-1C Gag突变途径。通过利用具有估计血清转化时间的前瞻性样本集并应用单基因组扩增/测序和超深度测序（在子集中），绘制HIV-1C Gag中病毒突变的出现时间、主导地位和完整性（或短暂性/丢失）。目标二：设计一系列免疫学相关假说，重点关注免疫应答与病毒突变途径之间的动态相互作用。具体的免疫学问题将根据实际的突变途径得到解决，因此，将改善现有的方法评估病毒特异性T细胞反应在原发性HIV感染，并将有助于探索相关的免疫保护机制在未来的研究。这项研究将揭示宿主-病毒相互作用的早期进化动力学，并可能使更好的免疫原设计成为可能。 公共卫生相关性：缺乏对保护的相关性的理解可能至少部分地在于，历史上病毒-宿主相互作用没有被交互地研究，而是专注于等式的一侧。该研究将采用一种新的方法，直接绘制Gag突变沿着HIV-1感染的时间线，并将评估病毒动力学模式，特别关注不同类型病毒突变之间的时间和关系。结果将被转化为一系列特定的免疫学假说，揭示病毒-宿主相互作用的机制。