AUTO-ANTI-CD4 ANTIBODIES IN HIV INFECTION

HIV 感染中的自身抗 CD4 抗体

• 批准号: 3147917
• 负责人: PILA ESTESS
• 金额: $ 13.36万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3147917
• 关键词: CD4 molecule; HIV envelope protein gp120; HIV infections; antiidiotype antibody; autoantibody; cell mediated lymphocytolysis test; cytotoxicity; gene mutation; genetic library; human immunodeficiency virus; human tissue; laboratory mouse; molecular cloning; nucleic acid sequence; protein structure; site directed mutagenesis; tissue /cell culture

The role of human CD4 as the receptor for human immunodeficiency virus (HIV) has led to extensive study of the molecular nature of CD4-gpl2O interactions. Data supports the hypothesis that anti-lymphocyte antibodies may play a critical role in the course of HIV disease, either protective or pathogenic. Sera from HIV infected individuals will be screened for anti-CD4 antibodies and those antibodies will be characterized for CD4 binding, blocking of a number of recombinant gpl2O's, and neutralization of infection by distinct viral isolates. The potential role of auto-anti-CD4 in the progression of HIV disease will be assessed by assaying the antisera for immunocytopathic effects. In addition, immunophenotypic profiles of select patients will be followed with particular attention to the presence of auto-antibodies bound to the surface of cells. Continued analyses of protein structure involved in expression of the antibody and envelope glycoprotein binding epitopes on CD4 are proposed using select CD4 mutants. Using these reagents, the molecular nature of interactions between auto-antibodies against CD4 arising during HIV infection will be investigated. The possible existence of molecular mimicry between autologous anti-CD4 antibodies and viral gpl2O will also be evaluated. From select individuals, anti-CD4 antibody producing lymphocytes will be used to generate combinatorial immunoglobulin expression libraries to clone and express the anti-CD4 antibodies. These recombinant Fab's will then be characterized structurally and mapped for binding to native and mutant CD4's. They will be analyzed for their ability to block different recombinant gpl2O's, and to inhibit viral infection in vitro. Structural information relevant to virus/CD4 interactions potentially useful for protection, immune intervention, and/or rational drug design will be obtained through these further molecular characterizations.

人CD4作为人类免疫缺陷病毒受体的作用 (HIV)导致了对cd4-gpl2O分子性质的广泛研究 互动。数据支持这样一种假设，即抗淋巴细胞 抗体也可能在艾滋病的发病过程中发挥关键作用。 保护性的或致病性的。来自艾滋病毒感染者的血清将是 对抗CD4抗体进行筛查，这些抗体将被 其特征为可与CD4结合，阻断多个重组 GPL2O，以及中和不同病毒分离株的感染。这个 自身抗体在HIV疾病进展中的潜在作用将是 通过检测抗血清的免疫细胞病变效应进行评估。在……里面 此外，还将跟踪选定患者的免疫表型特征。 需要特别注意的是是否存在与 细胞表面。继续分析涉及的蛋白质结构 抗体与包膜糖蛋白结合表位在日本血吸虫中的表达 建议使用精选的CD4突变体。使用这些试剂， 抗CD4自身抗体相互作用的分子本质 将对感染艾滋病毒期间产生的风险进行调查。可能的 自身抗CD_4抗体与CD_4间存在分子模拟 病毒gpl2O也将被评估。来自精选的个体，抗CD4 产生抗体的淋巴细胞将被用来产生组合 免疫球蛋白表达文库的克隆与表达 抗体。然后将对这些重组Fab进行表征 在结构上与天然和突变体CD4‘S结合。他们 将分析它们阻止不同重组体的能力 Gpl2O，并在体外抑制病毒感染。结构信息 与可能有助于保护的病毒/CD4相互作用有关， 免疫干预和/或合理的药物设计将通过 这些进一步的分子表征。