DAMPENING IMMUNODOMINANT EPITOPES

抑制免疫显性表位

• 批准号: 2756618
• 负责人: PETER Lloyd NARA
• 金额: $ 24.95万
• 依托单位: BIOLOGICAL MIMETICS, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2756618
• 关键词: AIDS vaccines; HIV envelope protein gp41; antigen presentation; cellular immunity; cytotoxic T lymphocyte; guinea pigs; human immunodeficiency virus 1; humoral immunity; immunogenetics; macrophage; monocyte; neutralizing antibody; protein engineering; protein structure function; recombinant proteins; recombinant virus; site directed mutagenesis; vaccine development; vaccinia virus

DESCRIPTION: (Adapted from applicant's abstract) The long- term objective of this research is to modify and improve the immunogenicity of the HIV-1 envelope protein in order to develop an efficacious HIV-1 vaccine. Infection with HIV-1 in the majority of people results in a chronic, active and progressive infection ultimately ending in death from opportunistic infections and/or cancer. Although a vigorous host response is elicited to the genetically unstable virus, the chronic active infection normally proceeds unchecked. The immune response is initially directed at limited epitopes on the viral envelope that are unusually immunodominant and ultimately non-protective. "Deceptive Imprinting," as it has become known, appears to have a decoying and short-circuiting effect on the immune system, and tends to prevent the immune system from directing its anti-viral activity toward more conserved and functional determinants involved in replication and/or pathogenesis. Recent research aimed at dampening or masking one of these immunodominant epitopes, V3, resulted in the development of a novel approach to shift the immune response to more conserved parts of the molecule. In these studies, a previously silent, second order series of immune responses, characterized by a broader degree of neutralization, were established. Additional hypervariable and immune thwarting epitopes have been identified in addition to the V3 domain. These occur in both the gpl20 and gp41 domains and are the focus of research in this proposal. Dampening these genetically variable and infection-enhancing epitopes will allow other more broadly protective epitopes to trigger the immune response. Thus, broadly neutralizing antibody and cell-mediated responses may be generated against primary HIV-1 isolates obtained from peripheral blood mononuclear cells (PBMCs) and macrophage cell types.

描述：（改编自申请人的摘要）长期目标 本研究的目的是修饰和提高HIV-1的免疫原性， 为了开发有效的HIV-1疫苗。 大多数人感染HIV-1后， 进行性感染最终死于机会性感染 感染和/或癌症。 虽然引起了强烈的宿主反应， 基因不稳定的病毒，慢性活动性感染通常 继续检查。 免疫反应最初是针对有限的 病毒包膜上的表位是异常免疫显性的， 最后是非保护性的。 众所周知的“欺骗性印记” 似乎对免疫系统有引诱和短路作用， 并倾向于阻止免疫系统将其抗病毒药物 活性向更保守的和功能性的决定因素参与， 复制和/或发病机制。 最近的研究旨在抑制或 掩蔽这些免疫显性表位之一V3，导致 开发一种新的方法，将免疫反应转移到更多 分子的保守部分。 在这些研究中， 二阶系列免疫反应，其特征在于更广泛的程度 中立化，已经建立。 额外的高变和免疫 除了V3结构域之外，还鉴定了阻碍表位。 这些 出现在gpl 20和gp 41域中，并且是研究的焦点 这个提议。 抑制这些遗传变异和感染增强 表位将允许其他更广泛的保护性表位触发 免疫反应 因此，广泛中和抗体和细胞介导的 可以产生针对从以下来源获得的主要HIV-1分离株的应答： 外周血单核细胞（PBMC）和巨噬细胞类型。