Complement Regulates the Humoral Response to HIV-1

描述(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。开发一种能诱导广泛反应的中和抗HIV抗体的疫苗至关重要，但到目前为止还没有有效的疫苗。已经从患者的单个B细胞中分离出几种这样的抗体，证明它们可以产生。这些抗体中有几种已被证明是多特异性的；它们除了与艾滋病毒反应外，还与多种抗原反应，它们类似于在被称为边缘地带(MZ)的脾部分形成的抗体。MZ的细胞是第一反应者，在有时间做出特定的免疫反应之前，它们会摧毁最初接种的病毒或细菌。MZ B细胞也可以被刺激迁移到脾内的B细胞滤泡，携带它们的抗原。在卵泡中，会产生一种更特异、高亲和力的抗体，就像艾滋病患者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。补体激活有三条途径。其中两项被证明是至关重要的。大多数病毒和细菌结合另一种补体途径的蛋白质。这些蛋白质被设计成靶向并帮助摧毁最初接种的微生物，甚至在特定抗体形成之前。大多数生物体不结合经典途径的蛋白质。我们进行了新的观察，即经典和替代补体途径将抗原定向到完全不同的细胞受体集合，并可以在体内介导不同的后果。经典途径蛋白的结合，但令人惊讶的是，不是替代途径蛋白，将抗原定向到MZ细胞上的C3d受体CD21。我们认为，HIV使用这种补体激活机制来调节其生命周期的关键阶段。经典的补体蛋白在触发MZ B细胞转移到毛囊生发中心的过程中扮演辅助因子的角色，在那里它们可以有效地将病毒转移到CD4T细胞。它们还会引发高度特异但不能广泛中和的抗体反应。MZ细胞的有效转移阻止了必要的MZ多特异性抗体反应，这是初始保护所必需的。抗原/抗体复合体中的抗体在免疫中起到佐剂的作用。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/抗体复合体作为疫苗，这一循环将被中断。MZ的细胞将产生适当的广泛中和、广泛特异的抗体反应，从而保护患者免受艾滋病毒感染。公共卫生相关性：开发一种有效的、广泛中和的抗艾滋病毒疫苗是国家优先事项。到目前为止，还没有一种疫苗能有效预防艾滋病毒感染。我们基于对补体在生物体生命周期中的作用的新理解，提出了一种产生有效艾滋病毒疫苗的新策略。

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.