IMMUNOTOXIN-DEPLETION OF HIV-1+T CELLS

HIV-1 T 细胞的免疫毒素耗竭

• 批准号: 6511507
• 负责人: ELLEN S VITETTA
• 金额: $ 31.29万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511507
• 关键词: AIDS therapy; T lymphocyte; antiAIDS agent; cell death; cell population study; cytotoxic T lymphocyte; cytotoxicity; drug screening /evaluation; flow cytometry; helper T lymphocyte; human immunodeficiency virus 1; human subject; human therapy evaluation; immunoconjugates; immunologic memory; immunotoxicity; indicator dilution test; patient oriented research; polymerase chain reaction; suppressor T lymphocyte

DESCRIPTION: We have previously demonstrated that an immunotoxin (IT) directed against CD45RO and containing chemically deglycosylated ricin toxin A chain (dgA), kills CD4-postive human T-cells which are both latently and actively infected with HIV-1 in vitro. We now propose to determine whether this IT can kill infected T-cells from HIV positive individuals and, in particular, latent cells from individuals receiving HAART. This study will involve perfecting a highly sensitive limiting dilution assay to determine the frequency of replication-competent cells. Experiments will include both in vitro- and in vivo-infected CD4-postive T cells infected with drug-resistant and drug-sensitive isolates of HIV-1. If the IT effectively kills the target cells, we will then determine what effect it has on immune memory in the CD4-positive and CD8-positive T-cell populations. This will be accomplished by treating peripheral blood cells from both HIV-negative and HIV-positive individuals with the IT and then activating cells with mitogens, superantigens, and antigens. Flow cytometry will then be used to evaluate intracellular cytokines in sub-populations of naive and memory CD4-postive and CD8-postive T-cells to determine whether T cell memory is compromised. This is a preclinical study to evaluate a new therapeutic modality. Our results should determine the feasibility of a future clinical trial.

描述：我们以前已经证明了一种免疫毒素（IT） 针对CD45RO，并含有化学脱糖基化的利西蛋白毒素A链 （DGA），杀死CD4-postive人类T细胞，它们既潜在地又积极地 体外感染HIV-1。我们现在建议确定是否可以 杀死来自艾滋病毒阳性个体的受感染的T细胞，尤其是潜在 来自接受HAART的个体的细胞。这项研究将涉及完善 高度敏感的限制稀释测定法，以确定 复制能力的细胞。实验将包括体外和 感染了耐药性和 HIV-1的药物敏感性分离株。如果它有效地杀死了目标细胞， 然后，我们将确定它对CD4阳性中免疫记忆的影响 和CD8阳性T细胞种群。这将通过治疗来实现 来自HIV阴性和HIV阳性个体的外周血细胞 IT，然后用有丝分裂原，超抗原和抗原激活细胞。 然后，流式细胞仪将用于评估细胞内细胞因子 幼稚和记忆CD4-postive和CD8-postive T细胞的子选集 确定T细胞存储器是否受到损害。这是一项临床前研究 评估一种新的治疗方式。我们的结果应确定 未来临床试验的可行性。