Complement Regulates the Humoral Response to HIV-1

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。开发一种疫苗，诱导广泛反应，中和抗艾滋病毒抗体是至关重要的，但迄今为止还没有疫苗是有效的。已经从患者的个体B细胞中分离出一些这样的抗体，证明它们可以产生。这些抗体中的几种已被证明是多特异性的;它们与除了HIV之外的多种抗原反应，并且它们类似于在称为边缘区（MZ）的脾脏部分中形成的抗体。MZ的细胞是第一反应者，并在有时间做出特异性免疫反应之前破坏病毒或细菌的初始接种物。也可以刺激MZ B细胞迁移到脾内的携带其抗原的B细胞滤泡。在卵泡中，产生了更特异、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。我们专注于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，也不会被杀死。补体激活有三种途径。其中两个是至关重要的。大多数病毒和细菌结合补体旁路途径的蛋白质。这些蛋白质被设计成靶向并帮助破坏最初的微生物接种物，甚至在特异性抗体形成之前。大多数生物体不结合经典途径的蛋白质。我们已经作出了新的观察，经典和替代补体途径直接抗原完全不同的细胞受体集，并可以介导不同的体内后果。经典途径蛋白的结合，但令人惊讶的是不是旁路途径蛋白，将抗原导向MZ细胞上的CD 21，C3 d受体。我们认为，HIV使用这种补体激活机制来介导其生命周期中的关键阶段。经典补体蛋白作为辅因子触发MZ B细胞转移到滤泡的生发中心，在那里它们被定位用于将病毒有效转移到CD 4 T细胞。它们还启动高度特异性但非广泛中和的抗体应答。MZ细胞的有效转移防止了初始保护所需的基本MZ多特异性抗体应答。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HIV抗原/抗体复合物作为疫苗，该复合物由仅激活补体旁路途径的抗体制备，该循环将被中断。MZ细胞将产生适当的广泛中和、广泛特异性抗体应答，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的优先事项。到目前为止，还没有疫苗能有效预防艾滋病毒感染。我们提出了一种新的策略，产生一个有效的艾滋病毒疫苗，基于一个新的理解的作用，补充在生命周期的有机体。

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.