GP120 VH3 SUPERANTIGEN AND HIV-1 PATHOGENESIS

描述(根据申请人的摘要)：HIV gp120最近被 被鉴定为免疫球蛋白超抗原(SAG)，与大多数成员结合 在大的VH3基因家族中(约占总血清的10% (免疫球蛋白)在非艾滋病毒感染者中。其中提出的概念 应用是，HIV已经进化出这种SAG来提高效率 在粘膜传播过程中的感染。初步研究表明 表明SAG结合抗体水平是一种多态宿主 特征，且对艾滋病毒高度易感个体对应 具有高表现型SAG结合性状的品种。这是初步的 这一发现支持高抗体表型是一种 HIV传播中的宿主易感因素。为了测试这一想法， 研究人员将确定这些抗体在体外是否会增强 通过Fcα受体依赖机制的感染及其类型 这一机制所针对的细胞。网关中SAG结合IgA水平的研究 将平行测量粘膜部位，并确定是否 易受粘膜传播影响的个体数量高 这些抗体的表达将被制造出来。家系和基因 还将进行研究，以确定遗传因素 有助于高表达的表型。矛盾的是，一个引人注目的 抗SAG抗体的优势也与长期相关 艾滋病毒感染的幸存者。为了理解这种相关性， 研究人员认为，抗gp120抗体也可能促进病毒传播。 携带Fcγ和/或C3R的细胞类型的摄取。因为这样的细胞是 主要是非T细胞，这可能有助于将病毒从T细胞重新定向 从而减少病毒的致病作用。初步的体外研究 展示了抗SAG IgM对gp120的免疫隔离作用。这个 最后两个目标用来进一步描述和验证这一点 保护机制有两个方面。首先，研究旨在 确定抗SAG免疫隔离是否抑制HIV感染 在体外，通过鉴定参与的受体和细胞类型， Gp120在外周血单核细胞中的免疫隔离作用及其机制 HIV感染T细胞的体外实验研究。第二，已经开发的试剂 操纵抗SAG活性将被用来测试抗SAG 免疫球蛋白抑制SCID-HU小鼠HIV致病作用。如果这些想法是 经过验证，那么这个项目将定义一个新的和重要的 HIV感染中的免疫遗传宿主因子和一类新的靶点 用于疫苗和其他保护性疗法的设计。

DESCRIPTION (based on applicant's abstract): HIV gp120 has recently been identified as an immunoglobulin superantigen (SAg), binding most members of the large VH3 gene family (approximately 10 percent of total serum IgM) in non-HIV-infected individuals. The concept put forth in this application is that HIV has evolved this SAg to enhance the efficiency of infection during mucosal transmission. Preliminary studies have shown that the level of SAg- binding antibodies is a polymorphic host trait, and that individuals highly susceptible to HIV correspond to those with the high phenotype SAg-binding trait. This preliminary finding supports the prediction that the high antibody phenotype is a host susceptibility factor in HIV transmission. To test this idea, the investigators will determine whether these antibodies enhance in vitro infection via an Fc alpha receptor-dependent mechanism and the types of cells targeted by this mechanism. Levels of SAg-binding IgA in gateway mucosal sites will be measured in parallel and determinations of whether individuals highly susceptible to mucosal transmission are high expressors for these antibodies will be made. Family and genotype studies will also be done to determine whether genetic factors contribute to the high expressor phenotype. Paradoxically, a striking predominance of anti-SAg antibodies is also associated with long term survivors of HIV infection. To understand this correlation, the investigators felt that anti-gp120 antibodies might also promote viral uptake by cell types bearing Fc gamma and/or C3R. Since such cells are mostly non-T cells, this may serve to redirect virus away from T cells and hence reduce viral pathogenesis. Initial in vitro studies demonstrate such immune sequestration of gp120 by anti-SAg IgM. The final two aims serve to further characterize and validate this protective mechanism in two ways. First, studies are designed to determine whether immune sequestration by anti-SAg inhibits HIV infection in vitro, through identifying the receptors and cell types involved in immune sequestration of gp120 in PBMCs, and the role of this mechanism on HIV infection of T cells in vitro. Second, reagents already developed to manipulate anti-SAg activity will be used to test whether anti-SAg Ig inhibits HIV pathogenesis in SCID-hu mice. If these ideas are validated, then this project will have defined a novel and important immunogenetic host factor in HIV infection, and a new class of target for the design of vaccines and other protective therapies.