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：我们之前已经证明，免疫毒素（IT）定向 抗CD45RO并含有化学去糖基化的蓖麻毒素A链 (dgA)，杀死潜伏和活跃的 CD4 阳性人类 T 细胞 体外感染HIV-1。我们现在建议确定该 IT 是否可以 杀死 HIV 阳性个体中受感染的 T 细胞，特别是潜伏的 T 细胞 来自接受HAART的个体的细胞。这项研究将涉及完善 高灵敏的有限稀释测定法可确定 有复制能力的细胞。实验将包括体外和体内 体内感染的CD4阳性T细胞感染了耐药性和 HIV-1 药物敏感分离株。如果IT有效地杀死目标细胞， 然后我们将确定它对 CD4 阳性的免疫记忆有何影响 和 CD8 阳性 T 细胞群。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，流式细胞术将用于评估细胞内细胞因子 幼稚和记忆 CD4 阳性和 CD8 阳性 T 细胞亚群 确定 T 细胞记忆是否受到损害。这是一项临床前研究 评估新的治疗方式。我们的结果应该决定 未来临床试验的可行性。