NON-NEUTRALIZING ANTIBODIES IN ACUTE PRIMARY HIV INFECTION

急性原发性 HIV 感染中的非中和抗体

• 批准号: 6201348
• 负责人: David C Montefiori
• 金额: $ 32.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201348
• 关键词: HIV infections; acute disease /disorder; antibody receptor; clearance rate; clinical research; complement pathway; complement receptor; human immunodeficiency virus 1; human subject; humoral immunity; immunoglobulin A; immunoglobulin G; immunoglobulin M; immunologic assay /test; longitudinal human study; microorganism immunology; receptor binding; virus infection mechanism; virus load; virus replication

A shortcoming of conventional assays used for the study of HIV-1-specific antibodies is that they often fail to detect activities associated with complement activation and Fc receptor binding that could influence virus replication in vivo. Complement-activating antibodies enhance the formation of complement-coated HIV-1 that resists complement lysis and binds complement receptors (CR) on a variety of cell types, including follicular dendritic cells, monocytes, macrophages, B lymphocyte and red blood cells. Antibody-coated virus may further interact with monocytes and macrophages through Fc receptors (FcR) independently of complement. Each of theses activities may be regulated by the immunoglobulin class and subclass and could influence HIV-1 replication in vivo by; 1) increasing virus entry or post-entry replication leading to infection-enhancement, 2) expanding tropism to cells that have little or no CD4 antigen on their surface, 3) trapping complement-opsonized virus on the surface of follicular dendritic cells and 4) clearing virus through the mononuclear phagocytic system. We will study immunologic mechanisms of complement activation and interactions of HIV-1 with CR and FcR during acute primary infection as a unique setting in which to explore their possible contribution to virus replication or clearance. One approach will be to determine whether complement activation in vivo correlates with immunological, virological and clinical profiles. Additional studies will characterize the appearance of circulating HIV-1 immune complexes and will assess whether their biochemical content and biological properties are predicted by serologic correlates. IgA, IgM and IgG production will be assessed to determine their timing of appearance and virus antigen specificity/ IgG will be further delineated with respect to subclasses. Antibodies will be assessed for complement activation using patient isolates and autologous sera in quantitative immunoassays. Infection- enhancement will be evaluated in assays that detect both complement- dependent and -independent mechanisms of antibody-enhanced HIV-1 infection. These studies will provide critical information on serological correlates of HIV-1 pathogenesis that predict interactions with CR and FcR involved in wither virus spread or in control of plasma viremia.

用于HIV-1特异性研究的常规测定的缺点是， 抗体的另一个缺点是，它们通常无法检测到与 补体激活和Fc受体结合可能影响病毒 体内复制 补体激活抗体增强 形成抵抗补体裂解的补体包被的HIV-1， 结合多种细胞类型上的补体受体（CR），包括 滤泡树突状细胞、单核细胞、巨噬细胞、B淋巴细胞和红细胞 血细胞 抗体包被的病毒可以进一步与单核细胞相互作用， 巨噬细胞通过Fc受体（FcR）独立于补体。 每个 这些活动的调节可能是由免疫球蛋白类， 亚类，并可通过以下方式影响HIV-1在体内的复制：1）增加 病毒进入或进入后复制导致感染增强，2） 将嗜性扩展到其上具有很少或没有CD 4抗原的细胞， 3）将补体调理的病毒捕获在 滤泡树突状细胞和4）通过单核细胞清除病毒 吞噬系统 我们将研究补体的免疫机制 HIV-1与CR和FcR的活化和相互作用 感染作为一个独特的环境中，探讨他们的可能 有助于病毒复制或清除。 一种方法是 确定体内补体激活是否与 免疫学、病毒学和临床特征。 其他研究将 表征循环HIV-1免疫复合物的外观，并将 评估其生化含量和生物特性是否 通过血清学相关性预测。 伊加、IgM和IgG的产生将是 评估以确定其出现时间和病毒抗原 特异性/ IgG将关于亚类进一步描述。 将使用患者血清评估抗体的补体激活 分离物和自体血清的定量免疫测定。 感染- 增强将在检测两种补体的测定中进行评价， 抗体增强HIV-1感染的依赖和非依赖机制。 这些研究将提供关于血清学相关性的关键信息 HIV-1发病机制，预测与CR和FcR的相互作用， 枯萎病毒传播或控制血浆病毒血症。