Understanding the antibody responses following Human Immunodeficiency Virus infection

了解人类免疫缺陷病毒感染后的抗体反应

• 批准号: 1214582
• 负责人: Stanca Ciupe
• 金额: $ 11.16万
• 依托单位: Virginia Polytechnic Institute and State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-10 至 2014-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1214582&HistoricalAwards=false
• 关键词: Understanding; antibody; responses; following; Human

During the course of an individual's infection with Human Immunodeficiency Virus (HIV), the virus population consists of a distribution of different variants, produced by mutation and selection. Consequently, the immune system attempts to build a response that is broad enough to handle the diversity of virus strains present. Biological experiments have shown that neutralizing antibodies fail to offer long-term protection because they are primarily strain-specific and lag behind viral evolution. The proposed research presents a thorough investigation of the antibody mediated immune responses against HIV with an emphasis on their neutralizing and non-neutralizing activity. Novel mathematical models of antibody responses following infection with HIV are developed, analyzed using asymptotic analysis, bifurcation analysis and numerical analysis, and validated against biological data in order to quantify the relative importance of biological processes in influencing disease evolution. The investigator aims to discover which factors (host or virus specific) influence the outcome of the infection. The specific goals are in understanding (1) the roles of competition and cross-reactivity between families of neutralizing antibodies in the presence and absence of virus evolution; (2) the necessity of antibodies to neutralize every viral spike; and (3) the role of non-neutralizing antibodies. All these questions will have implications for vaccine development as well as for disease prognosis.The ability of HIV to persist in an infected individual and eventually cause AIDS depends on its avoidance of the immune system. Of the two immune mechanisms present, the cellular response is better understood, while the antibody response is still under investigation. Understanding of how antibodies respond to the virus is crucial for the success of any future vaccine candidate, especially since current therapeutic vaccines focus on inducing both arms of the immune response. The goal of this proposal is to investigate how particular biological interactions can lead to an efficient antibody response during both immunization and natural infection with HIV. Given the difficulty and cost of experimentally examining all of the biological interactions involved, we consider alternative methods for testing new hypotheses. They consist of the development, analysis and validation against biological data of mathematical models, with the goal of providing insight into the dynamics of antibody responses. This knowledge may eventually guide treatment and prevention, and assist in establishing immunological goals for an effective AIDS vaccine. The research aims to promote the advancement of mathematical and biological knowledge, provide an opportunity for interdisciplinary collaboration with researchers in the mathematical and medical communities, and lead to the training of graduate and undergraduate students. The PI plans to incorporate ideas and results from the proposed research into a first year graduate Mathematical Biology course, as well as a summer course directed at undergraduate mathematics majors across Louisiana, and to engage with graduate and undergraduate students to incorporate this research as part of their dissertation and summer research programs.

在个人感染人类免疫缺陷病毒(HIV)的过程中，病毒群体由突变和选择产生的不同变种的分布组成。因此，免疫系统试图建立一种足够广泛的反应，以应对目前存在的病毒株的多样性。生物实验表明，中和抗体无法提供长期保护，因为它们主要是菌株特异性的，并且落后于病毒的进化。这项拟议的研究对抗体介导的针对HIV的免疫反应进行了彻底的研究，重点是它们的中和和非中和活性。建立了HIV感染后抗体反应的新的数学模型，用渐近分析、分歧分析和数值分析进行了分析，并用生物学数据进行了验证，以量化生物学过程在影响疾病进化中的相对重要性。研究人员的目标是发现哪些因素(宿主或病毒特有)影响感染的结果。具体目标是了解(1)在病毒进化存在和不存在的情况下中和抗体家族之间的竞争和交叉反应的作用；(2)抗体中和每个病毒尖峰的必要性；以及(3)非中和抗体的作用。所有这些问题都将对疫苗开发和疾病预后产生影响。艾滋病毒在感染者体内持续存在并最终导致艾滋病的能力取决于它对免疫系统的回避。在目前存在的两种免疫机制中，细胞反应得到了更好的理解，而抗体反应仍在研究中。了解抗体对病毒的反应对于任何未来的候选疫苗的成功都是至关重要的，特别是因为目前的治疗性疫苗侧重于诱导免疫反应的两个手臂。这项建议的目的是调查在免疫和自然感染艾滋病毒期间，特定的生物相互作用如何导致有效的抗体反应。考虑到在实验上检验所有涉及的生物相互作用的难度和成本，我们考虑了检验新假说的替代方法。它们包括数学模型的生物数据的开发、分析和验证，目的是提供对抗体反应动态的洞察。这些知识可能最终指导治疗和预防，并有助于建立有效的艾滋病疫苗的免疫学目标。这项研究旨在促进数学和生物知识的进步，为数学和医学界的研究人员提供跨学科合作的机会，并导致对研究生和本科生的培训。PI计划将拟议研究的想法和结果纳入一年级研究生数学生物学课程，以及针对路易斯安那州本科数学专业的暑期课程，并与研究生和本科生接触，将这项研究纳入他们的论文和暑期研究计划。