Complement Regulates the Humoral Response to HIV-1

补体调节对 HIV-1 的体液反应

• 批准号: 7764750
• 负责人: Michael M Frank
• 金额: $ 23.17万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764750
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adjuvant; Affect; Affinity; Alternative Complement Pathway; Antibodies; Antibody Affinity; Antibody Formation; Antigen-Antibody Complex; Antigens; B-Cell Activation; B-Lymphocytes; Bacteria; Binding; Binding Proteins; CD4 Positive T Lymphocytes; Cavia; Cell Lineage; Cell model; Cells; Chinese Hamster Ovary Cell; Classical Complement Pathway; Complement; Complement 3d Receptors; Complement Activation; Coupled; Development; Evolution; Failure; Fc Receptor; Flow Cytometry; Freezing; Generations; HIV; HIV Antibodies; HIV Antigens; HIV Infections; HIV vaccine; HIV-1; Human; Immune; Immune response; Immunization; Immunoglobulin G; Immunologic Receptors; Incidence; Individual; Infection; Life Cycle Stages; Literature; Lymphoid Tissue; Measures; Mediating; Microbe; Morbidity - disease rate; Mus; Organism; Pathway interactions; Patients; Phagocytosis; Play; Positioning Attribute; Property; Protein Binding; Proteins; Raji Cell; Retroviridae; Role; Signal Transduction; Site; Spleen; Spleen Part; Splenocyte; Staging; Structure of germinal center of lymph node; Surface; Time; Tissues; Up-Regulation; Vaccines; Virus; antigen binding; antimicrobial; base; citrate carrier; cofactor; complement pathway; design; emergency service responder; in vivo; killings; macrophage; mortality; neutralizing antibody; novel; novel vaccines; prevent; public health priorities; public health relevance; receptor; response; vaccine development

DESCRIPTION (provided by applicant): HIV/AIDS continues to cause enormous morbidity and mortality. Developing a vaccine that induces broadly reactive, neutralizing anti-HIV antibody is critically important, but so far no vaccine has been effective. A few such antibodies have been isolated from individual B cells of patients proving that they can be generated. Several of these antibodies have been shown to be polyspecific; they react with multiple antigens in addition to HIV, and they resemble antibodies formed in a part of the spleen termed the marginal zone (MZ). Cells of the MZ are first responders and act to destroy an initial inoculum of virus or bacteria before there is time to make a specific immune response. MZ B cells can also be stimulated to migrate to B cell follicles within the spleen, carrying their antigen. In the follicle, a more specific, high affinity antibody, like most of the antibody formed in AIDS patients, is generated. We focus on the known ability of HIV-1 and all retroviruses to mediate surface binding of proteins of the classical complement pathway, even in the absence of antibody, without being killed. There are three pathways of complement activation. Two of these prove critical. Most viruses and bacteria bind proteins of the alternative complement pathway. These proteins are designed to target and help destroy an initial inoculum of microbes, even before specific antibodies are formed. Most organisms do not bind proteins of the classical pathway. We have made the novel observation that the classical and alternative complement pathways direct antigens to entirely different sets of cellular receptors and can mediate different in vivo consequences. The binding of classical pathway proteins, but surprisingly not alternative pathway proteins, directs antigens to CD21, the C3d receptor, on MZ cells. We suggest that HIV uses this complement activating mechanism to mediate a critical stage in its life cycle. The classical complement proteins act as cofactors in triggering the transfer of MZ B-cells to the germinal center of the follicles where they are positioned for efficient transfer of virus to CD4 T cells. They also initiate a highly specific, but not broadly neutralizing, antibody response. The efficient transfer of MZ cells prevents the essential MZ polyspecific antibody response, required for initial protection. Antibody in antigen/antibody complexes is known to act as an adjuvant in immunization. We hypothesize that by using HIV antigen/antibody complexes prepared with antibodies that only activate the alternative complement pathway as a vaccine, the cycle will be interrupted. An appropriate broadly neutralizing, broadly specific antibody response will be generated by cells of the MZ, thus protecting patients from HIV infection. PUBLIC HEALTH RELEVANCE: The development of an effective, broadly neutralizing anti-HIV vaccine is a national priority. Thus far no vaccine has effectively prevented HIV infection. We propose a new strategy for the generation of an effective HIV vaccine, based on a new understanding of the role of complement in the life cycle of the organism.

描述（由申请人提供）：艾滋病毒/艾滋病继续造成巨大的发病率和死亡率。开发一种能够诱导广泛反应性、中和性抗艾滋病毒抗体的疫苗至关重要，但迄今为止还没有有效的疫苗。一些这样的抗体已经从患者的个体 B 细胞中分离出来，证明它们可以产生。其中一些抗体已被证明具有多特异性；除 HIV 外，它们还与多种抗原发生反应，并且类似于在称为边缘区 (MZ) 的脾脏部分中形成的抗体。 MZ 细胞是第一反应者，在有时间做出特定的免疫反应之前，会破坏病毒或细菌的初始接种物。 MZ B 细胞也可以被刺激迁移到脾内的 B 细胞滤泡，携带其抗原。在滤泡中，会产生一种更具特异性、高亲和力的抗体，就像艾滋病患者体内形成的大多数抗体一样。我们重点关注 HIV-1 和所有逆转录病毒介导经典补体途径蛋白质表面结合的已知能力，即使在没有抗体的情况下也不被杀死。补体激活有三种途径。其中两个被证明是至关重要的。大多数病毒和细菌结合补体替代途径的蛋白质。这些蛋白质旨在靶向并帮助破坏微生物的初始接种物，甚至在特定抗体形成之前也是如此。大多数生物体不结合经典途径的蛋白质。我们进行了新的观察，即经典补体途径和替代补体途径将抗原引导至完全不同的细胞受体组，并且可以介导不同的体内后果。经典途径蛋白（但令人惊讶的是替代途径蛋白）的结合将抗原引导至 MZ 细胞上的 CD21（C3d 受体）。我们认为艾滋病毒利用这种补体激活机制来介导其生命周期的关键阶段。经典的补体蛋白充当辅助因子，触发 MZ B 细胞转移到毛囊的生发中心，在那里它们将病毒有效转移到 CD4 T 细胞。它们还引发高度特异性但不广泛中和的抗体反应。 MZ 细胞的有效转移可防止初始保护所需的基本 MZ 多特异性抗体反应。已知抗原/抗体复合物中的抗体在免疫中充当佐剂。我们假设，通过使用仅激活替代补体途径的抗体制备的 HIV 抗原/抗体复合物作为疫苗，该循环将被中断。 MZ 细胞将产生适当的广泛中和、广泛特异性抗体反应，从而保护患者免受 HIV 感染。公共卫生相关性：开发有效的、广泛中和的抗艾滋病毒疫苗是国家优先事项。迄今为止，还没有疫苗能够有效预防艾滋病毒感染。基于对补体在生物体生命周期中的作用的新认识，我们提出了一种生产有效艾滋病毒疫苗的新策略。